Hydroxy-substituted aryl sulfamide derivatives and methods of their use

ABSTRACT

The present invention is directed to hydroxy-substituted aryl sulfamide derivatives of formula I: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, which are monoamine reuptake inhibitors, compositions containing these derivatives, and methods of their use for the prevention and treatment of conditions, including, inter alia, vasomotor symptoms, sexual dysfunction, gastrointestinal disorders and genitourinary disorder, depression disorders, endogenous behavioral disorders, cognitive disorders, diabetic neuropathy, pain, and other diseases or disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. §119(e) toco-pending U.S. Provisional Application Ser. No. 60/869,644, filed Dec.12, 2006, which is hereby incorporated by reference in its entirety.

FIELD

The present invention relates to hydroxy-substituted aryl sulfamidederivatives, which are monoamine reuptake inhibitors, compositionscontaining these derivatives, and methods of their use for theprevention and treatment of diseases or disorders including vasomotorsymptoms, depression disorders, endogenous behavioral disorders,cognitive disorders, sexual dysfunction, or pain conditions, inparticular vasomotor symptoms.

BACKGROUND

Vasomotor symptoms (VMS), referred to as hot flushes and night sweats,are the most common symptoms associated with menopause, occurring in 60%to 80% of all women following natural or surgically-induced menopause.VMS are likely an adaptive response of the central nervous system (CNS)to declining sex steroids. To date, the most effective therapies for VMSare hormone-based treatments, including estrogens and/or someprogestins. Hormonal treatments are very effective at alleviating VMS,but they are not appropriate for all women.

VMS are caused by fluctuations of sex steroid levels and can bedisruptive and disabling in both males and females. A hot flush can lastup to thirty minutes and vary in their frequency from several times aweek to multiple occurrences per day. The patient experiences a hotflush as a sudden feeling of heat that spreads quickly from the face tothe chest and back and then over the rest of the body. It is usuallyaccompanied by outbreaks of profuse sweating, and may sometimes occurseveral times an hour, and it often occurs at night. Hot flushes andoutbreaks of sweats occurring during the night can cause sleepdeprivation. Psychological and emotional symptoms are also observed,such as nervousness, fatigue, irritability, insomnia, depression, memoryloss, headache, anxiety, nervousness or inability to concentrate, andare caused by the sleep deprivation following hot flush and night sweats(Kramer et al., In: Murphy et al., 3^(rd) Int'l Symposium on RecentAdvances in Urological Cancer Diagnosis and Treatment-Proceedings,Paris, France: SCI: 3-7 (1992)).

Hot flushes may be even more severe in women treated for breast cancerfor several reasons. Many survivors of breast cancer are giventamoxifen, the most prevalent side effect of which is hot flush, andmany women treated for breast cancer undergo premature menopause fromchemotherapy Women with a history of breast cancer are also generallybeen denied estrogen therapy because of concerns about potentialrecurrence of breast cancer (Loprinzi, et al., Lancet, 2000, 356(9247):2059-2063).

Men also experience hot flushes following steroid hormone (androgen)withdrawal. This is true in cases of age-associated androgen decline(Katovich, et al., Proceedings of the Society for Experimental Biology &Medicine, 1990, 193(2): 129-35) as well as in extreme cases of hormonedeprivation associated with treatments for prostate cancer (Berendsen,et al., European Journal of Pharmacology, 2001, 419(1): 47-54. As manyas one-third of these patients will experience persistent and frequentsymptoms severe enough to cause significant discomfort andinconvenience.

The precise mechanism of these vasomotor symptoms is unknown butgenerally is thought to represent disturbances to normal homeostaticmechanisms controlling thermoregulation and vasomotor activity(Kronenberg et al., “Thermoregulatory Physiology of Menopausal HotFlashes: A Review,” Can. J. Physiol. Pharmacol., 1987, 65:1312-1324).

The fact that estrogen treatment (e.g. estrogen replacement therapy)relieves the symptoms establishes the link between these symptoms and anestrogen deficiency. For example, the menopausal stage of life isassociated with a wide range of other acute symptoms as described aboveand these symptoms are generally estrogen responsive.

It has been suggested that estrogens may stimulate the activity of boththe norepinephrine (NE) and/or serotonin (5-HT) systems (J. Pharmacology& Experimental Therapeutics, 1986, 236(3) 646-652). It is hypothesizedthat estrogens modulate NE and 5-HT levels providing homeostasis in thethermoregulatory center of the hypothalamus. The descending pathwaysfrom the hypothalamus via brainstem/spinal cord and the adrenals to theskin are involved in maintaining normal skin temperature. The action ofNE and 5-HT reuptake inhibitors is known to impinge on both the CNS andperipheral nervous system (PNS). The pathophysiology of VMS is mediatedby both central and peripheral mechanisms and, therefore, the interplaybetween the CNS and PNS may account for the efficacy of dual actingSRI/NRIs in the treatment of thermoregulatory dysfunction. In fact, thephysiological aspects and the CNS/PNS involvement in VMS may account forthe lower doses proposed to treat VMS (Loprinzi, et al., Lancet, 2000,356:2059-2063; Stearns et al., JAMA, 2003, 289:2827-2834) compared todoses used to treat the behavioral aspects of depression. The interplayof the CNS/PNS in the pathophysiology of VMS supports the claims thatthe norepinephrine system could be targeted to treat VMS.

Although VMS are most commonly treated by hormone therapy, some patientscannot tolerate estrogen treatment (Berendsen, Maturitas, 2000, 36(3):155-164, Fink et al., Nature, 1996, 383(6598): 306). In addition,hormone replacement therapy is usually not recommended for women or menwith or at risk for hormonally sensitive cancers (e.g. breast orprostate cancer). Thus, non-hormonal therapies (e.g. fluoxetine,paroxetine [SRIs] and clonidine) are being evaluated clinically.WO9944601 discloses a method for decreasing hot flushes in a humanfemale by administering fluoxetine. Other options have been studied forthe treatment of hot flushes, including steroids, alpha-adrenergicagonists, and beta-blockers, with varying degree of success (Waldingeret al., Maturitas, 2000, 36(3): 165-168).

α₂—Adrenergic receptors play a role in thermoregulatory dysfunctions(Freedman et al., Fertility & Sterility, 2000, 74(1): 20-3). Thesereceptors are located both pre- and post-synaptically and mediate aninhibitory role in the central and peripheral nervous system. There arefour distinct subtypes of the adrenergic_(α2) receptors, i.e., areα_(2A), α_(2B), α_(2C) and α_(2D) (Mackinnon et al., TIPS, 1994, 15:119; French, Pharmacol. Ther., 1995, 68: 175). A non-selectα₂-adrenoceptor antagonist, yohimbine, induces a flush and anα₂-adrenergic receptor agonist, clonidine, alleviates the yohimbineeffect (Katovich, et al., Proceedings of the Society for ExperimentalBiology & Medicine, 1990, 193(2): 129-35, Freedman et al., Fertility &Sterility, 2000, 74(1): 20-3). Clonidine has been used to treat hotflush. However, using such treatment is associated with a number ofundesired side effects caused by high doses necessary to abate hot flushdescribed herein and known in the related arts.

Chronic pain comes in many forms, including visceral, inflammatory orneuropathic and crosses all therapeutic areas. It is a debilitatingcondition that exerts a high social cost in terms of productivity,economic impact and quality of life and current therapies have limitedefficacy. Currently, first-line pharmacological treatments forneuropathic pain (i.e., diabetic neuropathy and post-herpetic neuralgia)and fibromyalgia include off-label use of the tricyclic (TCA)antidepressants (e.g., amytriptyline) and anticonvulsants (e.g.,gabapentin) (Collins et al., J. Pain Symptom Manage. 2000, 20(6):449-58;and Marcus Expert Opin Pharmacother. 2003, 4(10): 1687-95.). However,these therapies are only effective in 30-50% of patients and produceonly a partial reduction in pain (˜50%). In addition, the clinicalbenefits of these therapies are often outweighed by the side effects,including dry mouth and sedation. Therefore, newer classes of compoundsincluding non-TCA antidepressants are being evaluated preclinically andclinically for chronic pain indications, and recently duloxetine wasapproved for the treatment of diabetic neuropathy. Although moretolerable than the older tricyclic antidepressants, these newercompounds are not devoid of side effects that include sexualdysfunction, weight gain and nausea.

While the precise pathophysiological mechanisms involved in thedevelopment and maintenance of chronic pain states are not fullyunderstood, the pathways involved in pain perception and modulation havebeen well described and characterized (Gebhart, In: Yaksh T L, editor.Spinal afferent processing, New York: Plenum, 1986. pp 391-416; Fields,et al., Annual Review of Neuroscience 1991, 14: 219-245; Fields, et al.In: Wall P D, Melzack R, editors. Textbook of pain, London: ChurchillLivingstone, 1999, pp 309-329; Millan, et al. Progress in Neurobiology;2002, 66:355-474). A major component of this descending pain inhibitorysystem involves the noradrenergic pathway (Zhuo, et al., Brain Research1991; 550:35-48; Holden, et al. Neuroscience 1999; 91: 979-990). It isassumed that norepinephrine (NE), and to a lesser extent serotonin(5-HT) reuptake inhibitor NRIs and SRIs, attenuate pain by preventingpresynaptic reuptake of NE/5-HT leading to increased postsynapticNE/5-HT levels and sustained activation of this descending paininhibitory pathway. A meta-analysis of antidepressants and neuropathicpain comparing the efficacy of known NRIs, mixed NRI/SRIs and SRIsdetermined that compounds with NRI activity were more effective inreducing pain, and that select SRIs did not significantly differ fromplacebo (Collins et al., J. Pain Symptom Manage. 2000, 20(6): 449-58).This analysis suggests that compounds with greater NRI versus SRIactivity will be more effective for the treatment of pain.

Given the complex multifaceted nature of pain and of thermoregulationand the interplay between the CNS and PNS in maintainingthermoregulatory the homeostasis, multiple therapies and approaches canbe developed to target the treatment of pain and vasomotor symptoms. Thepresent invention provides novel compounds and compositions containingthese compounds directed to these and other important uses.

SUMMARY

The present invention is directed to aryl sulfamide derivatives, whichare monoamine reuptake inhibitors, compositions containing thesederivatives, and methods of their use for the prevention and treatmentof conditions, including, inter alia, vasomotor symptoms (such as hotflush), sexual dysfunction (such as desire-related or arousal-relateddysfunction), gastrointestinal disorders and genitourinary disorder(such as stress incontinence or urge incontinence), chronic fatiguesyndrome, fibromyalgia syndrome, depression disorders (such as majordepressive disorder, generalized anxiety disorder, panic disorder,attention deficit disorder with or without hyperactivity, sleepdisturbance, and social phobia), diabetic neuropathy, pain, andcombinations thereof.

One aspect of the invention provides a compound of formula I:

-   -   or a tautomer or pharmaceutically acceptable salt thereof;    -   wherein:    -   n is an integer from 0 to 4;    -   m is an integer from 1 to 6;    -   X is —CH₂—;    -   R¹ is, independently at each occurrence, H, alkyl, alkoxy, halo,        CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl,        alkynyl, aryl, heteroaryl, alkylsulfoxide, alkylsulfone,        alkylsulfonamide, arylsulfonamide alkylamido, or arylamido;        wherein each aryl or heteroaryl is independently substituted        with 0-3 alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy,        nitro, nitrile, alkenyl, or alkynyl groups; and each        arylsulfonamide or arylamido is independently substituted with        0-3 alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro,        nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone,        alkylsulfonamide, or alkylamido groups;    -   R² is aryl or heteroaryl substituted with 0-4 alkyl, alkoxy,        halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl,        alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide,        arylsulfonamide, alkylamido, arylamido, or aryl or heteroaryl        optionally substituted with alkyl, alkoxy, halo, CF₃, OCF₃,        hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl;    -   R³ and R⁴ are, independently, H, alkyl, arylalkyl or        heteroarylmethyl, wherein each of alkyl, arylalkyl or        heteroarylmethyl are indepentyl substituted with 0-3 alkyl,        alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile,        alkenyl, or alkynyl groups, provided that neither R³ or R⁴        contain an aminoalkyl group;    -   represents an S-isomer, R-isomer or racemate; and    -   wherein 1-3 carbon atoms in ring A may optionally be replaced        with N.

Another aspect of the invention provides a composition, comprising:

a. at least one compound of formula I; and

b. at least one pharmaceutically acceptable carrier.

Another aspect of the invention provides a method for treating orpreventing a condition selected from the group consisting of a vasomotorsymptom, sexual dysfunction, gastrointestinal disorder, genitourinarydisorder, chronic fatigue syndrome, fibromyalgia syndrome, depressiondisorder, endogenous behavioral disorder, cognitive disorder, diabeticneuropathy, pain, and combinations thereof in a subject in need thereof,comprising the step of:

administering to said subject an effective amount of a compound offormula I.

Another aspect of the invention provides a process for the preparationof a compound of formula I:

the process comprising:

reacting HN(R³)(R⁴) a compound of formula IA:

wherein the compound of formula I is formed.

In another aspect of the invention, the compound of formula IA is formedby:

activating a primary or secondary hydroxy group on the compound offormula IB:

-   -   to form an activated compound of formula IB; and    -   contacting the activated compound of formula IB with a base,        wherein the compound of formula IA is formed.

In another aspect of the invention, the compound of formula IB is formedby:

deprotecting a compound of formula IC:

In another aspect of the invention, the compound of formula IC isprepared by:

oxidizing a compound of formula ID:

In another aspect of the invention, the compound of formula ID isprepared by:

reacting thionyl chloride (SOCl₂) with a compound of formula IE:

In another aspect of the invention, the compound of formula IE isprepared by:

reacting a compound of formula IF:

with a compound of formula IG:

wherein, the compound of formula IE is formed.

Other objects, features and advantages of the present invention willbecome apparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples, while indicating embodiments of the invention, are given byway of illustration only, since various changes and modifications withinthe spirit and scope of the invention will become apparent to thoseskilled in the art from this detailed description.

DETAILED DESCRIPTION

The following definitions are provided for the full understanding ofterms and abbreviations used in this specification.

As used herein and in the appended claims, the singular forms “a,” “an,”and “the” include the plural reference unless the context clearlyindicates otherwise. Thus, for example, a reference to “an antagonist”includes a plurality of such antagonists, and a reference to “acompound” is a reference to one or more compounds and equivalentsthereof known to those skilled in the art, and so forth.

The abbreviations in the specification correspond to units of measure,techniques, properties, or compounds as follows: “min” means minutes,“h” means hour(s), “μL” means microliter(s), “mL” means milliliter(s),“mM” means millimolar, “M” means molar, “mmole” means millimole(s), “cm”means centimeters, “SEM” means standard error of the mean and “IU” meansInternational Units. “Δ° C.” and Δ “ED₅₀ value” means dose which resultsin 50% alleviation of the observed condition or effect (50% mean maximumendpoint).

“Norepinephrine transporter” is abbreviated NET.

“Human norepinephrine transporter” is abbreviated hNET.

“Serotonin transporter” is abbreviated SERT.

“Human serotonin transporter” is abbreviated hSERT.

“Norepinephrine reuptake inhibitor” is abbreviated NRI.

“Selective norepinephrine reuptake inhibitor” is abbreviated SNRI.

“Serotonin reuptake inhibitor” is abbreviated SRI.

“Selective serotonin reuptake inhibitor” is abbreviated SSRI.

“Norepinephrine” is abbreviated NE.

“Serotonin is abbreviated 5-HT.

“Subcutaneous” is abbreviated sc.

“Intraperitoneal” is abbreviated ip.

“Oral” is abbreviated po.

In the context of this disclosure, a number of terms are utilized. Theterm “treat,” “treatment” or “treating” as used herein includespreventative (e.g., prophylactic), curative or palliative treatment.

The term “effective amount,” as used herein, refers to an amounteffective, at dosages, and for periods of time necessary, to achieve thedesired result with respect to treatment of a given disease or disorder.An effective amount is also one in which any toxic or detrimentaleffects of the components are outweighed by the therapeuticallybeneficial effects. In particular, with respect to vasomotor symptoms,“effective amount” refers to the amount of compound or composition ofcompounds that would increase norepinephrine levels to compensate inpart or total for the lack of steroid availability in subjects subjectafflicted with a vasomotor symptom. Varying hormone levels willinfluence the amount of compound required in the present invention. Forexample, the pre-menopausal state may require a lower level of compounddue to higher hormone levels than the peri-menopausal state.

The effective amount of components of the present invention will varyfrom patient to patient not only with the particular compound, componentor composition selected, the route of administration, and the ability ofthe components (alone or in combination with one or more additionalactive agents) to elicit a desired response in the individual, but alsowith factors such as the disease state or severity of the condition tobe alleviated, hormone levels, age, sex, weight of the individual, thestate of being of the patient, and the severity of the pathologicalcondition being treated, concurrent medication or special diets thenbeing followed by the particular patient, and other factors which thoseskilled in the art will recognize, with the appropriate dosageultimately being at the discretion of the attendant physician. Dosageregimens may be adjusted to provide the improved therapeutic response.

Preferably, the compounds of the present invention are administered at adosage and for a time such that the number of hot flushes is reduced ascompared to the number of hot flushes prior to the start of treatment.Such treatment can also be beneficial to reduce the overall severity orintensity distribution of any hot flushes still experienced, as comparedto the severity of hot flushes prior to the start of the treatment. Withrespect to sexual dysfunction, gastrointestinal disorder, genitourinarydisorder, chronic fatigue syndrome, fibromyalgia syndrome, depressiondisorder, diabetic neuropathy, or pain, the compounds of the presentinvention are administered at a dosage and for a time sufficient totreat the symptom or condition.

For example, for a patient, compounds of formula I, or apharmaceutically acceptable salt thereof, may be administered,preferably, at a dosage of from about 0.1 mg/day to about 1500 mg/day,dosed one or two times daily, more preferably from about 1 mg/day toabout 200 mg/day and most preferably from about 1 mg/day to 100 mg/dayfor a time sufficient to reduce and/or substantially eliminate thenumber and/or severity of hot flushes or symptom or condition of thesexual dysfunction, gastrointestinal disorder, genitourinary disorder,chronic fatigue syndrome, fibromyalgia syndrome, depression disorder,diabetic neuropathy, or pain.

The terms “component,” “composition,” “composition of compounds,”“compound,” “drug,” or “pharmacologically active agent” or “activeagent” or “medicament” are used interchangeably herein to refer to acompound or compounds or composition of matter which, when administeredto a subject (human or animal) induces a desired pharmacological and/orphysiologic effect by local and/or systemic action.

The term “modulation” refers to the capacity to either enhance orinhibit a functional property of a biological activity or process; forexample, receptor binding or signaling activity. Such enhancement orinhibition may be contingent on the occurrence of a specific event, suchas activation of a signal transduction pathway and/or may be manifestonly in particular cell types. The modulator is intended to comprise anycompound; e.g., antibody, small molecule, peptide, oligopeptide,polypeptide, or protein, and is preferably small molecule, or peptide.

As used herein, the term “inhibitor” refers to any agent that inhibits,suppresses, represses, or decreases a specific activity, such asnorepinephrine reuptake activity. The term “inhibitor” is intended tocomprise any compound; e.g., antibody, small molecule, peptide,oligopeptide, polypeptide, or protein (preferably small molecule orpeptide) that exhibits a partial, complete, competitive and/orinhibitory effect on mammalian (preferably the human) norepinephrinereuptake or both serotonin reuptake and the norepinephrine reuptake,thus diminishing or blocking (preferably diminishing) some or all of thebiological effects of endogenous norepinephrine reuptake or of bothserotonin reuptake and the norepinephrine reuptake.

Within the present invention, the compounds of formula I, may beprepared in the form of pharmaceutically acceptable salts. As usedherein, the term “pharmaceutically acceptable salts” refers to saltsprepared from pharmaceutically acceptable non-toxic acids, includinginorganic salts and organic salts. Suitable non-organic salts includeinorganic and organic acids such as acetic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic,hydrobromic, hydrochloric, isethionic, lactic, malic, maleic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric acid, p-toluenesulfonic and the like.Particularly preferred are hydrochloric, hydrobromic, phosphoric, andsulfuric acids, and most preferred is the hydrochloride salt.

“Administering,” as used herein, means either directly administering acompound or composition of the present invention, or administering aprodrug, derivative or analog which will form an equivalent amount ofthe active compound or substance within the body.

The term “subject” or “patient” refers to an animal including the humanspecies that is treatable with the compounds, compositions, and/ormethods of the present invention. The term “subject” or “subjects” isintended to refer to both the male and female gender unless one genderis specifically indicated. Accordingly, the term “patient” comprises anymammal which may benefit from treatment or prevention of a disease ordisorder, such as a human, especially if the mammal is female, either inthe pre-menopausal, peri-menopausal, or post-menopausal period.Furthermore, the term patient includes female animals including humansand, among humans, not only women of advanced age who have passedthrough menopause but also women who have undergone hysterectomy or forsome other reason have suppressed estrogen production, such as those whohave undergone long-term administration of corticosteroids, suffer fromCushing's syndrome or have gonadal dysgenesis. However, the term“patient” is not intended to be limited to a woman.

“Side effect” refers to a consequence other than the one(s) for which anagent or measure is used, as one or more adverse effects produced by adrug, especially on a tissue or organ system other then the one soughtto be benefited by its administration. In the case, for example, of highdoses of NRIs or NRI/SRI compounds alone, the term “side effect” mayrefer to such conditions as, for example, vomiting, nausea, sweating,and hot flushes (Janowsky, et al., Journal of Clinical Psychiatry, 1984,45(10 Pt 2): 3-9).

“Vasomotor symptoms,” (also called “vasomotor instability symptoms” and“vasomotor disturbances”) include, but are not limited to, hot flushes(flushes), insomnia, sleep disturbances, mood disorders, irritability,excessive perspiration, night sweats, fatigue, and the like, caused by,inter alia, thermoregulatory dysfunction.

The term “hot flush” (sometimes called “hot flash”) is an art-recognizedterm that refers to an episodic disturbance in body temperaturetypically consisting of a sudden skin flushing, usually accompanied byperspiration in a subject.

The terms “premature menopause” or “artificial menopause” refer toovarian failure of unknown cause that may occur before age 40. It may beassociated with smoking, living at high altitude, or poor nutritionalstatus. Artificial menopause may result from oophorectomy, chemotherapy,radiation of the pelvis, or any process that impairs ovarian bloodsupply.

The term “pre-menopausal” means before the menopause, the term“peri-menopausal” means during the menopause and the term“post-menopausal” means after the menopause. “Ovariectomy” means removalof an ovary or ovaries and can be effected according to Merchenthaler etal., Maturitas, 1998, 30(3): 307-316.

The term “sexual dysfunction” includes, but is not limited to,conditions relating to disorders of sexual desire and/or arousal.

As used herein, “gastrointestinal and genitourinary disorders” includesirritable bowel syndrome, symptomatic GERD, hypersensitive esophagus,nonulcer dyspepsia, noncardiac chest pain, biliary dyskinesia, sphincterof Oddi dysfunction, incontinence (i.e., urge incontinence, stressincontinence, genuine stress incontinence, and mixed incontinence,including the involuntary voiding of feces or urine, and dribbling orleakage or feces or urine which may be due to one or more causesincluding but not limited to pathology altering sphincter control, lossof cognitive function, overdistention of the bladder, hyperreflexiaand/or involuntary urethral relaxation, weakness of the musclesassociated with the bladder or neurologic abnormalities), interstitialcystitis (irritable bladder), and chronic pelvic pain (including, butnot limited to vulvodynia, prostatodynia, and proctalgia).

As used herein, “chronic fatigue syndrome” (CFS) is a conditioncharacterized by physiological symptoms selected from weakness, muscleaches and pains, excessive sleep, malaise, fever, sore throat, tenderlymph nodes, impaired memory and/or mental concentration, insomnia,disordered sleep, localized tenderness, diffuse pain and fatigue, andcombinations thereof, whether or not correlated with Epstein-Barr virusinfection.

As used herein, “fibromyalgia syndrome” (FMS) includes FMS and othersomatoform disorders, including FMS associated with depression,somatization disorder, conversion disorder, pain disorder,hypochondriasis, body dysmorphic disorder, undifferentiated somatoformdisorder, and somatoform NOS. FMS and other somatoform disorders areaccompanied by physiological symptoms selected from a generalizedheightened perception of sensory stimuli, abnormalities in painperception in the form of allodynia (pain with innocuous stimulation),abnormalities in pain perception in the form of hyperalgesia (increasedsensitivity to painful stimuli), and combinations thereof.

As used herein, the term “depression disorder” includes major depressivedisorder, generalized anxiety disorder, panic disorder, attentiondeficit disorder with or without hyperactivity, sleep disturbance,social phobia, and combinations thereof.

The compounds of the present invention can also be used to treat acognitive disorder or an endogenous behavioral disorder. As used herein,a “cognitive disorder” includes changes or defects in alertness; mildcognitive impairment (MCI), characterized by problems with memory,language, or other mental functions which is severe enough to benoticeable or be detected by tests, but not serious enough tosignificantly interfere with daily life; cognitive disorder NOS (nototherwise specified), characterized by a syndrome of cognitiveimpairment that does not meet the criteria for delerium, dementia oramnesic disorders; age-related cognitive decline (ARCD); and cognitivearousal (such as increased arousal states). A cognition disorder can beideopathic, or can be caused by a variety of other factors such as acongenital defect, alcohol or drug addiction, transient or permanentpharmacologic effects of drugs, organic or infectious disease (e.g.,Alzheimer's disease, Parkinson's disease, AIDS), trauma (e.g., braininjury, stroke) or advanced age. As used herein, an “endogenousbehavioral disorder” includes attention deficit disorder/attentiondeficit hyperactivity disorder (ADD/ADHD, including adult and pediatricforms of predominantly inattentive, predominantly hyperactive, orcombined types), obsessive-compulsive disorder (OCD), oppositional oroppositional explosive defiant disorder (ODD/OEDD), anxiety and panicdisorders (APD) and temper, rage and outburst behavior disorder (TROBD).

As used herein, “pain” includes both acute and chronic nociceptic orneuropathic pain, which includes centralized pain, peripheral pain, orcombination thereof. The term includes many different types of pain,including, but not limited to, visceral pain, musculoskeletal pain, bonypain, cancer pain, inflammatory pain, and combinations thereof, such aslower back pain, atypical chest pain, headache such as cluster headache,migraine, herpes neuralgia, phantom limb pain, pelvic pain, myofascialface pain, abdominal pain, neck pain, central pain, dental pain, opioidresistant pain, visceral pain, surgical pain, bone injury pain, painduring labor and delivery, pain resulting from burns, post partum pain,angina pain, peripheral neuropathy and diabetic neuropathy,post-operative pain, and pain which is co-morbid with nervous systemdisorders described herein.

As used herein, the term “acute pain” refers to centralized orperipheral pain that is intense, localized, sharp, or stinging, and/ordull, aching, diffuse, or burning in nature and that occurs for shortperiods of time.

As used herein, the term “chronic pain” refers to centralized orperipheral pain that is intense, localized, sharp, or stinging, and/ordull, aching, diffuse, or burning in nature and that occurs for extendedperiods of time (i.e., persistent and/or regularly reoccurring),including, for the purposes of the present invention, neuropathic painand cancer pain. Chronic pain includes neuropathic pain, hyperalgesia,and/or allodynia.

As used herein, the term “neuropathic pain” refers to chronic paincaused by damage to or pathological changes in the peripheral or centralnervous systems. Examples of pathological changes related to neuropathicpain include prolonged peripheral or central neuronal sensitization,central sensitization related damage to nervous system inhibitory and/orexhibitory functions and abnormal interactions between theparasympathetic and sympathetic nervous systems. A wide range ofclinical conditions may be associated with or form the basis forneuropathic pain including, for example, diabetes, post traumatic painof amputation (nerve damage cause by injury resulting in peripheraland/or central sensitization such as phantom limb pain), lower backpain, cancer, chemical injury, toxins, other major surgeries, peripheralnerve damage due to traumatic injury compression, post-herpeticneuralgia, trigeminal neuralgia, lumbar or cervical radiculopathies,fibromyalgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy,casualgia, thalamic syndrome, nerve root avulsion, reflex sympatheticdystrophy or post thoracotomy pain, nutritional deficiencies, or viralor bacterial infections such as shingles or human immunodeficiency virus(HIV), and combinations thereof. Also included in the definition ofneuropathic pain is a condition secondary to metastatic infiltration,adiposis dolorosa, burns, central pain conditions related to thalamicconditions, and combinations thereof.

As used herein, the term “hyperalgesia” refers to pain where there is anincrease in sensitivity to a typically noxious stimulus.

As used herein, the term “allodynia” refers to an increase insensitivity to a typically non-noxious stimulus.

As used herein, the term “visceral pain” refers to pain associated withor resulting from maladies of the internal organs, such as, for example,ulcerative colitis, irritable bowel syndrome, irritable bladder, Crohn'sdisease, rheumatologic (arthralgias), tumors, gastritis, pancreatitis,infections of the organs, biliary tract disorders, and combinationsthereof.

As used herein, the term “female-specific pain” refers to pain that maybe acute and/or chronic pain associated with female conditions. Suchgroups of pain include those that are encountered solely orpredominately by females, including pain associated with menstruation,ovulation, pregnancy or childbirth, miscarriage, ectopic pregnancy,retrograde menstruation, rupture of a follicular or corpus luteum cyst,irritation of the pelvic viscera, uterine fibroids, adenomyosis,endometriosis, infection and inflammation, pelvic organ ischemia,obstruction, intra-abdominal adhesions, anatomic distortion of thepelvic viscera, ovarian abscess, loss of pelvic support, tumors, pelviccongestion or referred pain from non-gynecological causes, andcombinations thereof.

“Alkyl,” as used herein, refers to an optionally substituted, saturatedstraight, branched, or cyclic hydrocarbon having from about 1 to about20 carbon atoms (and all combinations and subcombinations of ranges andspecific numbers of carbon atoms therein), with from about 1 to about 8carbon atoms or 1 to 6 carbon atoms (C₁-C₆) being preferred, and withfrom about 1 to about 4 carbon atoms, herein referred to as “loweralkyl”, being more preferred. Alkyl groups include, but are not limitedto, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl,n-pentyl, cyclopentyl, cyclopropyl, isopentyl, neopentyl, n-hexyl,isohexyl, cyclohexyl, cyclooctyl, adamantyl, 3-methylpentyl,2,2-dimethylbutyl, and 2,3-dimethylbutyl. A branched alkyl group has atleast 3 carbon atoms (e.g., an isopropyl group), and in variousembodiments, has up to 6 carbon atoms, i.e., a branched lower alkylgroup. A branched alkyl group has at least 3 carbon atoms (e.g., anisopropyl group), and in various embodiments, has up to 6 carbon atoms,i.e., a branched lower alkyl group. Examples of branched lower alkylgroups include, but are not limited to:

“Alkenyl,” as used herein, refers to an alkyl group of at least twocarbon atoms having one or more double bonds, wherein alkyl is asdefined herein. Preferred alkenyl groups have from 2 to 6 carbon atoms(C₂-C₆). Alkenyl groups can be optionally substituted.

“Alkynyl,” as used herein, refers to an alkyl group of at least twocarbon atoms having one or more triple bonds, wherein alkyl is asdefined herein. Preferred alkynyl groups have from 2 to 6 carbon atoms(C₂-C₆). Alkynyl groups can be optionally substituted.

“Alkylenyl”, “alkenylenyl”, “alkynylenyl”, and “arylenyl” refer to thesubsets of alkyl, alkenyl, alkynyl and aryl groups, respectively, asdefined herein, including the same residues as alkyl, alkenyl, alkynyl,and aryl but having two points of attachment within a chemicalstructure. Examples of C₁-C₆alkylenyl include methylenyl (—CH₂—),ethylenyl (—CH₂CH₂—), propylenyl (—CH₂CH₂CH₂—), and dimethylpropylenyl(—CH₂C(CH₃)₂CH₂—). Likewise, examples of C₂-C₆alkenylenyl includeethenylenyl (—CH═CH— and propenylenyl (—CH═CH—CH₂—). Examples ofC₂-C₆alkynylenyl include ethynylenyl (—C≡C—) and propynylenyl(—C≡C—CH₂—).

Examples of arylenyl groups include phenylenyl;

Preferably, arylenyl groups contain 6 carbon atoms (C₆).

“Halo,” as used herein, refers to chloro, bromo, fluoro, and iodo.

“Aryl” as used herein, refers to an optionally substituted, mono-, di-,tri-, or other multicyclic aromatic ring system having from about 5 toabout 50 carbon atoms (and all combinations and subcombinations ofranges and specific numbers of carbon atoms therein), with from about 6to about 10 carbons (C₆-C₁₀) being preferred. Non-limiting examplesinclude, for example, phenyl, naphthyl, anthracenyl, and phenanthrenyl.

“Heteroaryl,” as used herein, refers to an optionally substituted,mono-, di-, tri-, or other multicyclic aromatic ring system thatincludes at least one, and preferably from 1 to about 4 heteroatom ringmembers selected from sulfur, oxygen and nitrogen. Heteroaryl groups canhave, for example, from about 3 to about 50 carbon atoms (and allcombinations and subcombinations of ranges and specific numbers ofcarbon atoms therein), with from about 4 to about 10 carbons beingpreferred. Non-limiting examples of heteroaryl groups include, forexample, pyrryl, furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl,isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl,isoquinolyl, thiophenyl, benzothienyl, isobenzofuryl, pyrazolyl,indolyl, purinyl, carbazolyl, benzimidazolyl, and isoxazolyl.

“Heterocyclic ring,” as used herein, refers to a stable 4- to12-membered monocyclic or bicyclic or 7- to 10-membered bicyclicheterocyclic ring that is saturated, partially unsaturated orunsaturated (aromatic), and which contains carbon atoms and from 1 to 4heteroatoms independently selected from the group consisting of N, O andS and including any bicyclic group in which any of the above definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurheteroatoms may optionally be oxidized. The heterocyclic ring may beattached to its pendant group at any heteroatom or carbon atom thatresults in a stable structure. The heterocyclic rings described hereinmay be substituted on carbon or on a nitrogen atom if the resultingcompound is stable. If specifically noted, a nitrogen atom in theheterocycle may optionally be quaternized. It is preferred that when thetotal number of S and O atoms in the heterocycle exceeds one, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than two.Examples of heterocycles include, but are not limited to, 1H-indazole,2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl,4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,carbazolyl, 4H-carbazolyl, α-, β-, or γ-carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl,isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylpyrimidinyl,phenanthridinyl, phenanthrolinyl, phenoxazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl,pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, xanthenyl. Preferred heterocycles include, but are notlimited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl,imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl,benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinyl.Also included are fused ring and spiro compounds containing, forexample, the above heterocycles.

“Alkoxy,” as used herein, refers to the group R—O— where R is an alkylgroup, as defined herein. Preferred alkoxy groups have from 1 to 6carbon atoms (C₁-C₆).

“Arylalkyl,” as used herein, refers to the group R′—R— where R′ is anaryl group, as defined herein, and R is an alkyl group, as definedherein. Preferred arylalkyl groups have from 7 to 16 carbon atoms(C₇-C₁₆).

“Heteroarylalkyl,” as used herein, refers to the group R″-R— where R″ isa heteroaryl group, as defined herein, and R is an alkyl group, asdefined herein.

“Heteroarylmethyl,” as used herein, refers to the group R″—CH₂— where R″is a heteroaryl group, as defined herein.

“Alkanoyloxy,” as used herein, refers to the group R—C(═O)—O— where R isan alkyl group, as defined herein, of 1 to 5 carbon atoms (C₁-C₅).

“Alkylsulfoxide,” as used herein, refers to as used herein, refers to—S(═O)—R′, where R′ is alkyl, as defined herein. Preferred alkysulfoxidegroups have from 1 to 6 carbon atoms (C₁-C₆).

“Arylsulfoxide,” as used herein, refers to as used herein, refers to—S(═O)—R′, where R′ is aryl, as defined herein. Preferred arylsulfoxidegroups have from 6 to 10 carbon atoms (C₆-C₁₀).

“Alkylsulfone,” as used herein, refers to —S(═O)₂—R′, where R′ is alkyl,as defined herein. Preferred alkylsulfone groups have from 1 to 6 carbonatoms (C₁-C₆).

“Arylsulfone,” as used herein, refers to —S(═O)₂—R′, where R′ is aryl,as defined herein. Preferred arylsulfone groups have from 6 to 10 carbonatoms (C₆-C₁₀).

“Alkylsulfonamide,” as used herein, refers to —NR—S(═O)₂—R, where each Ris independently, alkyl, as defined above, or the NR part may also beNH. Preferred alkylsulfonamide groups have from 1 to 6 carbon atoms(C₁-C₆).

“Arylsulfonamide,” as used herein, refers to —NR—S(═O)₂—R′, where R is Hor alkyl, as defined herein, and R′ is aryl, as defined herein.Preferred arylsulfonamide groups have from 6 to 10 carbon atoms(C₆-C₁₀).

“Heteroarylsulfonamide,” as used herein, refers to —NR—S(═O)₂—R″, whereR is H or alkyl, as defined herein, and R″ is aryl, as defined herein.

“Alkylamido,” as used herein, refers to —NR—C(═O)—R′, where each R isindependently, alkyl, as defined above, or the NR part may also be NH.Preferred alkylamido groups have from 1 to 6 carbon atoms (C₁-C₆).

“Arylamido,” as used herein, refers to —NR—C(═O)—R″, where R is H oralkyl, as defined herein, and R″ is aryl, as defined herein. Preferredarylamido groups have from 6 to 10 carbon atoms (C₆-C₁₀).

“Phenylamido,” as used herein, refers to —NR—C(═O)-phenyl, where R is Hor alkyl, as defined above.

As used herein, the terms “optionally substituted” or “substituted orunsubstituted” are intended to refer to the optional replacement of upto four hydrogen atoms with up to four independently selectedsubstituent groups as defined herein. Unless otherwise specified,suitable substituent groups independently include hydroxyl, nitro,amino, imino, cyano, halo, thio, sulfonyl, aminocarbonyl, carbonylamino,carbonyl, oxo, guanidine, carboxyl, formyl, alkyl, perfluoroalkyl,alkylamino, dialkylamino, alkoxy, alkoxyalkyl, alkylcarbonyl,arylcarbonyl, alkylthio, aryl, heteroaryl, a heterocyclic ring,cycloalkyl, hydroxyalkyl, carboxyalkyl, haloalkyl, alkenyl, alkynyl,arylalkyl, aryloxy, heteroaryloxy, heteroarylalkyl, and the like.Substituent groups that have one or more available hydrogen atoms can inturn optionally bear further independently selected substituents, to amaximum of three levels of substitutions. For example, the term“optionally substituted alkyl” is intended to mean an alkyl group thatcan optionally have up to four of its hydrogen atoms replaced withsubstituent groups as defined above (i.e., a first level ofsubstitution), wherein each of the substituent groups attached to thealkyl group can optionally have up to four of its hydrogen atomsreplaced by substituent groups as defined above (i.e., a second level ofsubstitution), and each of the substituent groups of the second level ofsubstitution can optionally have up to four of its hydrogen atomsreplaced by substituent groups as defined above (i.e., a third level ofsubstitution).

Unless indicated otherwise, the nomenclature of substituents that arenot explicitly defined herein are arrived at by naming the terminalportion of the functionality followed by the adjacent functionalitytoward the point of attachment. For example, the substituent“arylalkoxycabonyl” refers to the group (aryl)-(alkyl)-O—C(O)—.

It is understood that the above definitions are not intended to includeimpermissible substitution patterns (e.g., methyl substituted with 5fluoro groups). Such impermissible substitution patterns are well knownto the skilled artisan.

At various places in the present specification, substituents ofcompounds are disclosed in groups or in ranges. It is specificallyintended that the description include each and every individualsubcombination of the members of such groups and ranges. For example,the term “C₁₋₆ alkyl” is specifically intended to individually discloseC₁, C₂, C₃, C₄, C₅, C₆, C₁-C₆, C₁-C₅, C₁-C₄, C₁-C₃, C₁-C₂, C₂-C₆, C₂-C₅,C₂-C₄, C₂-C₃, C₃-C₆, C₃-C₅, C₃-C₄, C₄-C₆, C₄-C₅, and C₅-C₆ alkyl. By wayof another example, the term “5-9 membered heteroaryl group” isspecifically intended to individually disclose a heteroaryl group having5, 6, 7, 8, 9, 5-9, 5-8, 5-7, 5-6, 6-9, 6-8, 6-7, 7-9, 7-8, and 8-9 ringatoms.

The term “protecting group” or “G_(p)” with respect to amine groups,hydroxyl groups and sulfhydryl groups refers to forms of thesefunctionalities which are protected from undesirable reaction with aprotecting group known to those skilled in the art, such as those setforth in Protective Groups in Organic Synthesis, Greene, T. W.; Wuts, P.G. M., John Wiley & Sons, New York, N.Y., (3rd Edition, 1999) which canbe added or removed using the procedures set forth therein. Examples ofprotected hydroxyl groups include, but are not limited to, silyl etherssuch as those obtained by reaction of a hydroxyl group with a reagentsuch as, but not limited to, t-butyldimethyl-chlorosilane,trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane;substituted methyl and ethyl ethers such as, but not limited tomethoxymethyl ether, methylthiomethyl ether, benzyloxymethyl ether,t-butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranylethers, 1-ethoxyethyl ether, allyl ether, benzyl ether; esters such as,but not limited to, benzoylformate, formate, acetate, trichloroacetate,and trifluoracetate. Examples of protected amine groups include, but arenot limited to, amides such as, formamide, acetamide,trifluoroacetamide, and benzamide; carbamates; e.g. BOC; imides, such asphthalimide, Fmoc, Cbz, PMB, benzyl, and dithiosuccinimide; and others.Examples of protected or capped sulfhydryl groups include, but are notlimited to, thioethers such as S-benzyl thioether, and S-4-picolylthioether; substituted S-methyl derivatives such as hemithio, dithio andaminothio acetals; and others.

Reference to “activated” or “an activating group” or “G_(a)” as usedherein indicates having an electrophilic moiety bound to a substituent,capable of being displaced by a nucleophile. Examples of preferredactivating groups are halogens, such as Cl, Br or I, and F; triflate;mesylate, or tosylate; esters; aldehydes; ketones; epoxides; and thelike. An example of an activated group is acetylchloride, which isreadily attacked by a nucleophile, such as piperidine group to form aN-acetylpiperidine functionality.

The term “deprotecting” refers to removal of a protecting group, such asremoval of a benzyl or BOC group bound to an amine. Deprotecting may bepreformed by heating and/or addition of reagents capable of removingprotecting groups. In preferred embodiments, the deprotecting stepinvolves addition of an acid, base, reducing agent, oxidizing agent,heat, or any combination thereof. One preferred method of removing BOCgroups from amino groups is to add HCl in ethyl acetate. Manydeprotecting reactions are well known in the art and are described inProtective Groups in Organic Synthesis, Greene, T. W., John Wiley &Sons, New York, N.Y., (1st Edition, 1981), the entire disclosure ofwhich is herein incorporated by reference.

One aspect of the invention provides a compound of formula I:

-   -   or a tautomer or pharmaceutically acceptable salt thereof;    -   wherein:    -   n is an integer from 0 to 4;    -   m is an integer from 1 to 6;    -   X is —CH₂—;    -   R¹ is, independently at each occurrence, H, alkyl, alkoxy, halo,        CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl,        alkynyl, aryl, heteroaryl, alkylsulfoxide, alkylsulfone,        alkylsulfonamide, arylsulfonamide alkylamido, or arylamido;        wherein each aryl or heteroaryl is independently substituted        with 0-3 alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy,        nitro, nitrile, alkenyl, or alkynyl groups; and each        arylsulfonamide or arylamido is independently substituted with        0-3 alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro,        nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone,        alkylsulfonamide, or alkylamido groups;    -   R² is aryl or heteroaryl substituted with 0-4 alkyl, alkoxy,        halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl,        alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide,        arylsulfonamide, alkylamido, arylamido, or aryl or heteroaryl        optionally substituted with alkyl, alkoxy, halo, CF₃, OCF₃,        hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl;    -   R³ and R⁴ are, independently, H, alkyl, arylalkyl or        heteroarylmethyl, wherein each of alkyl, arylalkyl or        heteroarylmethyl are indepentyl substituted with 0-3 alkyl,        alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile,        alkenyl, or alkynyl groups, provided that neither    -   R³ or R⁴ contain an aminoalkyl group;    -   represents an S-isomer, R-isomer or racemate; and    -   wherein 1-3 carbon atoms in ring A may optionally be replaced        with N.

In another embodiment, each R¹ is H.

In another embodiment, R² is:

wherein,

each R⁵, R⁶, R⁷, R⁸ and R⁹ are independently selected from the groupconsisting of H, alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy,nitro, nitrile, alkenyl, alkynyl, aryl substituted, heteroaryl,alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide,alkylamido, or arylamido.

In another embodiment, R⁹ is F. In another embodiment, R⁵, R⁶, R⁷ and R⁸are H. In another embodiment R⁵ is H or F, R⁶ is H or F, R⁷ is H or F,R⁸ is H or F and R⁹ is H or F. In another embodiment, R⁵, R⁶, R⁷, R⁸ andR⁹ are H, halo, alkyl or alkoxy.

In another embodiment, R³ is alkyl. More particularly, methyl.

In another embodiment, R⁴ is H.

In another embodiment, m is an integer from 2 to 6. More particularly, mis 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 5, 2 to 4, 2 to 3, 3 to 6, 3 to5, 3 to 4, 4 to 6, or 4 to 5. In another embodiment, m is 1, m is 2, mis 3, m is 4, m is 5 or m is 6.

In another embodiment, ring A comprises all carbon atoms.

In another embodiment, R² is pyridinyl, methyl-pyridinyl,ethyl-pyridinyl, methoxy-pyridinyl, or quinolinyl.

In another embodiment, R² is phenyl, fluoro-phenyl, difluoro-phenyl,trifluoro-phenyl, chloro-phenyl, fluoro-chloro-phenyl, bromo-phenyl,trifluoromethyl-phenyl trifluoromethoxy-phenyl, methyl-fluoro-phenyl,methoxy-fluoro-phenyl, or naphthyl.

In another embodiment,

represents an S-isomer. Alternatively,

represents an R-isomer. Alternatively,

represents a racemate.

In another embodiment:

-   -   R¹ is H;    -   R⁹ is F;    -   R⁵, R⁶, R⁷ and R⁸ are H;    -   R³ is methyl;    -   R⁴ is H;    -   m is 2; and    -   represents an S-isomer.

In another embodiment, the compound is selected from the groupconsisting of:

Another aspect of the invention provides a compound selected from thegroup consisting of:

-   1-amino-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;-   (2R)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;-   (2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;-   3-fluoro-4-{3-[(3S)-3-hydroxy-4-(methylamino)butyl]-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl}phenol:-   4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;-   5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)pentan-2-ol;-   (2S)-1-amino-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;-   (2S)-5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)pentan-2-ol;-   (2R)-5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)pentan-2-ol;-   4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(ethylamino)butan-2-ol;-   1-(dimethylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol;-   4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(isopropylamino)butan-2-ol;-   1-(cyclopropylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol;-   1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol;-   4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylamino)butan-2-ol;-   (2R)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylamino)butan-2-ol;-   (2S)-1-(dimethylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol;-   (2R)-1-(dimethylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol;-   (2S)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(isopropylamino)butan-2-ol;-   (2R)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(isopropylamino)butan-2-ol;-   (2S)-1-(cyclopropylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol;-   (2S)-1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol;-   (2R)-1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol;-   (2S)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(ethylamino)butan-2-ol;-   (2R)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(ethylamino)butan-2-ol;-   (2S)-1-(cyclopropylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;-   (2S)-1-(cyclopropylamino)-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;-   (2S)-1-(cyclopropylamino)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;-   (2S)-1-(cyclopropylamino)-4-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;-   (2S)-1-(cyclopropylamino)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;-   (2S)-1-(cyclopropylamino)-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;-   (2S)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylamino)butan-2-ol;-   (2S)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;-   (2S)-4-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;-   (2S)-4-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;-   (2S)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;-   (2S)-4-[3-(4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;-   (2S)-1-(methylamino)-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;-   (2S)-4-[3-(2-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;-   (2S)-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;-   (2R)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;-   (2R)-4-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;-   (2R)-4-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;-   (2R)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;-   (2R)-4-[3-(4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;-   (2R)-1-(methylamino)-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;-   (2R)-4-[3-(2-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;-   (2R)-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;-   (2S)-1-(cyclobutylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;-   (2S)-1-(cyclopentylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;-   (2S)-1-(cyclohexylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;-   (2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(isopropylamino)butan-2-ol;-   (2S)-1-(ethylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;    and

pharmaceutically acceptable salts thereof.

In another embodiment, said pharmaceutically acceptable salt is ahydrochloride or dihydrochloride.

Another aspect of the invention provides a composition, comprising:

a. at least one compound of formula I; and

b. at least one pharmaceutically acceptable carrier.

Another aspect of the invention provides a method for treating orpreventing a condition selected from the group consisting of a vasomotorsymptom, sexual dysfunction, gastrointestinal disorder, genitourinarydisorder, chronic fatigue syndrome, fibromyalgia syndrome, depressiondisorder, endogenous behavioral disorder, cognitive disorder, diabeticneuropathy, pain, and combinations thereof in a subject in need thereof,comprising the step of:

administering to said subject an effective amount of a compound offormula I.

In certain embodiments, the vasomotor symptom is hot flush.

In certain embodiments, the sexual dysfunction is desire-related orarousal-related.

In certain embodiments, the gastrointestinal disorder or thegenitourinary disorder is stress incontinence or urge incontinence.

In certain embodiments, the condition is chronic fatigue syndrome.

In certain embodiments, the condition is fibromyalgia syndrome.

In certain embodiments, the condition is a depression disorder selectedfrom the group consisting of major depressive disorder, generalizedanxiety disorder, panic disorder, attention deficit disorder with orwithout hyperactivity, sleep disturbance, social phobia, andcombinations thereof.

In certain embodiments, the disorder is an endogenous behavioraldisorder or a cognitive disorder.

In certain embodiments, the condition is diabetic neuropathy.

In certain embodiments, the condition is pain.

In certain embodiments, the pain is acute centralized pain, acuteperipheral pain, or a combination thereof.

In certain embodiments, the pain is chronic centralized pain, chronicperipheral pain, or a combination thereof.

In certain embodiments, the pain is neuropathic pain, visceral pain,musculoskeletal pain, bony pain, cancer pain, inflammatory pain, or acombination thereof.

In certain embodiments, the neuropathic pain is associated withdiabetes, post traumatic pain of amputation, lower back pain, cancer,chemical injury, toxins, major surgery, peripheral nerve damage due totraumatic injury compression, post-herpetic neuralgia, trigeminalneuralgia, lumbar or cervical radiculopathies, fibromyalgia,glossopharyngeal neuralgia, reflex sympathetic dystrophy, casualgia,thalamic syndrome, nerve root avulsion, reflex sympathetic dystrophy orpost thoracotomy pain, nutritional deficiencies, viral infection,bacterial infection, metastatic infiltration, adiposis dolorosa, burns,central pain conditions related to thalamic conditions, or a combinationthereof.

In certain embodiments, the neuropathic pain is post-herpetic neuralgia.

In certain embodiments, the visceral pain is associated with ulcerativecolitis, irritable bowel syndrome, irritable bladder, Crohn's disease,rheumatologic (arthralgias), tumors, gastritis, pancreatitis, infectionsof the organs, biliary tract disorders, or a combination thereof.

In certain embodiments, the pain is female-specific pain.

The present invention provides a treatment for vasomotor symptoms bymethods of recovering the reduced activity of norepinephrine. Withoutwishing to be bound by any theory, norepinephrine activity in thehypothalamus or in the brainstem can be elevated by (i) blocking theactivity of the NE transporter, (ii) blocking the activity of thepresynaptic adrenergic_(α2) receptor with an antagonist, or (iii)blocking the activity of 5-HT on NE neurons with a 5-HT_(2a) antagonist.

The compounds of the invention are also useful to prevent and treatpain. The pain may be, for example, acute pain or chronic pain. The painmay also be centralized or peripheral.

Examples of pain that can be acute or chronic and that can be treated inaccordance with the methods of the present invention includeinflammatory pain, musculoskeletal pain, bony pain, lumbosacral pain,neck or upper back pain, visceral pain, somatic pain, neuropathic pain,cancer pain, pain caused by injury or surgery such as burn pain ordental pain, or headaches such as migraines or tension headaches, orcombinations of these pains. One skilled in the art will recognize thatthese pains may overlap one another. For example, a pain caused byinflammation may also be visceral or musculoskeletal in nature.

In a preferred embodiment of the present invention the compounds usefulin the present invention are administered in mammals to treat chronicpain such as neuropathic pain associated for example with damage to orpathological changes in the peripheral or central nervous systems;cancer pain; visceral pain associated with for example the abdominal,pelvic, and/or perineal regions or pancreatitis; musculoskeletal painassociated with for example the lower or upper back, spine,fibromyalgia, temporomandibular joint, or myofascial pain syndrome; bonypain associated with for example bone or joint degenerating disorderssuch as osteoarthritis, rheumatoid arthritis, or spinal stenosis;headaches such migraine or tension headaches; or pain associated withinfections such as HIV, sickle cell anemia, autoimmune disorders,multiple sclerosis, or inflammation such as osteoarthritis or rheumatoidarthritis.

In a more preferred embodiment, the compounds useful in this inventionare used to treat chronic pain that is neuropathic pain, visceral pain,musculoskeletal pain, bony pain, cancer pain or inflammatory pain orcombinations thereof, in accordance with the methods described herein.Inflammatory pain can be associated with a variety of medical conditionssuch as osteoarthritis, rheumatoid arthritis, surgery, or injury.Neuropathic pain may be associated with for example diabetic neuropathy,peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia,lumbar or cervical radiculopathies, fibromyalgia, glossopharyngealneuralgia, reflex sympathetic dystrophy, casualgia, thalamic syndrome,nerve root avulsion, or nerve damage cause by injury resulting inperipheral and/or central sensitization such as phantom limb pain,reflex sympathetic dystrophy or postthoracotomy pain, cancer, chemicalinjury, toxins, nutritional deficiencies, or viral or bacterialinfections such as shingles or HIV, or combinations thereof. The methodsof use for compounds of this invention further include treatments inwhich the neuropathic pain is a condition secondary to metastaticinfiltration, adiposis dolorosa, burns, or central pain conditionsrelated to thalamic conditions.

As mentioned previously, the methods of the present invention may beused to treat pain that is somatic and/or visceral in nature. Forexample, somatic pain that can be treated in accordance with the methodsof the present invention include pains associated with structural orsoft tissue injury experienced during surgery, dental procedures, burns,or traumatic body injuries. Examples of visceral pain that can betreated in accordance with the methods of the present invention includethose types of pain associated with or resulting from maladies of theinternal organs such as ulcerative colitis, irritable bowel syndrome,irritable bladder, Crohn's disease, rheumatologic (arthralgias), tumors,gastritis, pancreatitis, infections of the organs, or biliary tractdisorders, or combinations thereof. One skilled in the art will alsorecognize that the pain treated according to the methods of the presentinvention may also be related to conditions of hyperalgesia, allodynia,or both. Additionally, the chronic pain may be with or withoutperipheral or central sensitization.

The compounds useful in this invention may also be used to treat acuteand/or chronic pain associated with female conditions, which may also bereferred to as female-specific pain. Such groups of pain include thosethat are encountered solely or predominately by females, including painassociated with menstruation, ovulation, pregnancy or childbirth,miscarriage, ectopic pregnancy, retrograde menstruation, rupture of afollicular or corpus luteum cyst, irritation of the pelvic viscera,uterine fibroids, adenomyosis, endometriosis, infection andinflammation, pelvic organ ischemia, obstruction, intra-abdominaladhesions, anatomic distortion of the pelvic viscera, ovarian abscess,loss of pelvic support, tumors, pelvic congestion or referred pain fromnon-gynecological causes.

Another aspect of the invention provides a process for the preparationof a compound of formula I:

the process comprising:

reacting HN(R³)(R⁴) a compound of formula IA:

wherein the compound of formula I is formed.

In another aspect of the invention, the compound of formula IA is formedby:

activating a primary or secondary hydroxy group on the compound offormula IB:

-   -   to form an activated compound of formula IB; and    -   contacting the activated compound of formula IB with a base,        wherein the compound of formula IA is formed.

In another embodiment, the activating step comprises:

tosylating the primary hydroxy group on the compound of formula IB.

In another aspect of the invention, the compound of formula IB is formedby:

deprotecting a compound of formula IC:

In another embodiment, the deprotecting step comprises:

contacting the compound of formula IC with an acid.

In another embodiment, the acid is hydrochloric acid (HCl).

In another aspect of the invention, the compound of formula IC isprepared by:

oxidizing a compound of formula ID:

In another embodiment, the oxidizing step is performed in the presenceof sodium periodate (NaIO₄) and ruthenium chloride (RuCl₃).

In another aspect of the invention, the compound of formula ID isprepared by:

reacting thionyl chloride (SOCl₂) with a compound of formula IE:

In another embodiment, the reacting step is performed in the presence oftriethylamine (Et₃N).

In another aspect of the invention, the compound of formula IE isprepared by:

reacting a compound of formula IF:

with a compound of formula IG:

wherein, the compound of formula IE is formed.

In another embodiment, the reacting step is performed in the presence ofsodium cyanoborohydride (NaCNBH₃) and acetic acid (AcOH).

In another embodiment, the reacting step:

-   -   is performed at or above 30° C.;    -   is performed in a protic solvent, an aprotic solvent, a polar        solvent, a nonpolar solvent, a protic polar solvent, an aprotic        nonpolar solvent, or an aprotic polar solvent; or    -   includes a purification step comprising at least one of:        filtration, extraction, chromatography, trituration, or        recrystallization.

Some of the compounds of the present invention may contain chiralcenters and such compounds may exist in the form of stereoisomers (i.e.enantiomers or diastereomers). The present invention includes all suchstereoisomers and any mixtures thereof including racemic mixtures.Racemic mixtures of the stereoisomers as well as the substantially purestereoisomers are within the scope of the invention. The term“substantially pure,” as used herein, refers to at least about 90 mole%, more preferably at least about 95 mole %, and most preferably atleast about 98 mole % of the desired stereoisomer is present relative toother possible stereoisomers. Preferred enantiomers may be isolated fromracemic mixtures by any method known to those skilled in the art,including high performance liquid chromatography (HPLC) and theformation and crystallization of chiral salts or prepared by methodsdescribed herein. See, for example, Jacques, et al., Enantiomers,Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen,S. H., et al., Tetrahedron, 33:2725 (1977); Eliel, E. L. Stereochemistryof Carbon Compounds, (McGraw-Hill, NY, 1962); Wilen, S. H. Tables ofResolving Agents and Optical Resolutions, p. 268 (E. L. Eliel, Ed.,University of Notre Dame Press, Notre Dame, IN 1972), the entiredisclosures of which are herein incorporated by reference.

The present invention includes prodrugs of the compounds of formula I.“Prodrug,” as used herein, means a compound which is convertible in vivoby chemical or metabolic means (e.g. by hydrolysis) to a compound offormula I. Various forms of prodrugs are known in the art, for example,as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985);Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press(1985); Krogsgaard-Larsen, et al., (ed). “Design and Application ofProdrugs,” Textbook of Drug Design and Development, Chapter 5, 113-191(1991), Bundgaard, et al., Journal of Drug Deliver Reviews, 1992,8:1-38, Bundgaard, J. of Pharmaceutical Sciences, 1988, 77:285 et seq.;and Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems,American Chemical Society (1975), the entire disclosures of which areherein incorporated by reference.

Further, the compounds of formula I may exist in unsolvated as well asin solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like. In general, the solvated forms areconsidered equivalent to the unsolvated forms for the purpose of thepresent invention.

The compounds of the present invention may be prepared in a number ofways well known to those skilled in the art. The compounds can besynthesized, for example, by the methods described below, or variationsthereon as appreciated by the skilled artisan. All processes disclosedin association with the present invention are contemplated to bepracticed on any scale, including milligram, gram, multigram, kilogram,multikilogram or commercial industrial scale.

As will be readily understood, functional groups present may containprotecting groups during the course of synthesis. Protecting groups areknown per se as chemical functional groups that can be selectivelyappended to and removed from functionalities, such as hydroxyl groupsand carboxyl groups. These groups are present in a chemical compound torender such functionality inert to chemical reaction conditions to whichthe compound is exposed. Any of a variety of protecting groups may beemployed with the present invention. Protecting groups that may beemployed in accordance with the present invention may be described inGreene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis2d. Ed., Wiley & Sons, 1991, the entire disclosure of which is hereinincorporated by reference.

Compounds of the present invention are suitably prepared in accordancewith the following general description and specific examples. Variablesused are as defined for formula I, unless otherwise noted. The reagentsused in the preparation of the compounds of this invention can be eithercommercially obtained or can be prepared by standard proceduresdescribed in the literature. In accordance with this invention,compounds of formula I may be produced by the following reaction schemes(Schemes 1-3).

The compounds of this invention contain chiral centers, providing forvarious stereoisomeric forms such as diastereomeric mixtures,enantiomeric mixtures as well as optical isomers. The individual opticalisomers can be prepared directly through asymmetric and/orstereospecific synthesis or by conventional chiral separation of opticalisomers from the enantiomeric mixture.

Following Scheme 1, an appropriate fluoronitroarene 1 may be substitutedwith an aryl amine using a base under standard conditions to provide anaminonitroarene 2. Typically conditions for this reaction a base such assodium hydride in DMF or an organometallic base such as butyllithium inTHF. Reduction of the nitro group in structure 2 is accomplished understandard conditions using hydrogen and a suitable catalyst such aspalladium or Raney nickel to provide a dianiline 3. Nitro reduction is acommon transformation and one could employ a number of alternativeprocedures including reduction conditions using metal salts such asaqueous HCl with tin(II) chloride or aqueous ammonium chloride with zincmetal. The dianiline 3 is then treated a suitable sulfate containingreagent to form arylsulfamide of structure 4. In a typical example, 3was heated with sulfamide in diglyme to provide the cyclized product 4.The acidic nitrogen is then combined with a suitably substituted sidechain providing products 5 or 6 defending on the structure of thedesired side chain. An effective method for attaching the side chain tosulfamide 4 is the Mitsunobu reaction in which an alcohol is activatedand displaced by treating with a phosphine and an activating reagent. Inaccordance with the embodiment of the invention, typical conditions foreffecting the attachment of the sulfamide to the alcohol containing sidechain were treatment with diisopropyl azodicarboxylate andtriphenylphosphine in THF. Another suitable method for accomplishingside chain attachment is direct nucleophilic substitution of a leavinggroup containing side chain with the sulfamide and can be facilitated byaddition of a base in a suitable solvent. Typically compounds ofstructure 5 with a bromine containing side chain were treated with anexcess of the desired amine to provide the desired compounds of formulaI. An alternative method for the synthesis of compounds of formula I ispossible from 6 where the side chain is attached with the amine presentin protected form (the protecting group is represented by the letter P).Any suitable amine protecting group, t-butoxycarbonyl in a typicalexample, may be used. The protecting group is then removed, in the caseof t-butoxycarbonyl using an acid such as hydrochloric acid, to givecompounds of formula I.

An additional method for the synthesis of compounds of formula I isdescribed in Scheme 2. An appropriate fluoronitroarene is substitutedwith an amine bearing the desired side chain to give compounds ofstructure 7. Reduction of the nitro group under conditions described inScheme 1 provides 8. Compounds of structure 8 can be converted toarylsulfamide of structure 9 by treatment with a suitable sulfatecontaining reagent. In a typical example, 8 was heated with sulfamide indiglyme to provide the cyclized product 9. An aryl group may then beattached to the sulfamide 9 using conventional methods for formation ofan aryl-nitrogen bond. In a typical example an aryl boronic acid formsan aryl-nitrogen bond in the presence of a transition metal salt such ascopper(II) acetate to provide 6. Subsequent deprotection of theprotecting group P in 6 affords compounds of formula I. As described inScheme 1, the protecting group t-butoxycarbonyl was useful for thispurpose and is readily removed using an acid such as hydrochloric acidto give compounds of formula I.

Following Scheme 3, dianiline 3 can be treated with an aldehyde usingstandard reductive amination conditions giving substituted dianiline 11.Condensation of this with thionyl chloride under basic conditions givesthe sulfonylurea 12 which can be readily oxidized utilizing a variety ofconditions to the sulfamide 13. Treatment of this with hydrogen chlorideunmasks the diol 14 which is converted to the tosylate 15 under basicconditions. When treated with potassium carbonate this is readilyconverted to the epoxide 16 which can be treated with an excess of thedesired amine to provide the desired compounds of formula 17.

Scheme 4

Following Scheme 4, sulfamide 4, prepared as in Scheme 1, can be readilyalkylated with an epoxide containing a leaving group including but notlimited to bromide, tosylate or mesylate providing compounds ofstructure 16. Typically compounds of structure 16 were treated with anexcess of the desired amine to provide the desired compounds of formula1.

In other embodiments, the invention is directed to pharmaceuticalcompositions, comprising:

-   a. at least one compound of formula I, or pharmaceutically    acceptable salt thereof; and-   b. at least one pharmaceutically acceptable carrier.

Generally, the compound of formula I, or a pharmaceutically acceptablesalt thereof, will be present at a level of from about 0.1%, by weight,to about 90% by weight, based on the total weight of the pharmaceuticalcomposition, based on the total weight of the pharmaceuticalcomposition. Preferably, the compound of formula I, or apharmaceutically acceptable salt thereof, will be present at a level ofat least about 1%, by weight, based on the total weight of thepharmaceutical composition. More preferably, the compound of formula I,or a pharmaceutically acceptable salt thereof, will be present at alevel of at least about 5%, by weight, based on the total weight of thepharmaceutical composition. Even more preferably, the compound offormula I, or a pharmaceutically acceptable salt thereof will be presentat a level of at least about 10%, by weight, based on the total weightof the pharmaceutical composition. Yet even more preferably, thecompound of formula I, or a pharmaceutically acceptable salt thereof,will be present at a level of at least about 25%, by weight, based onthe total weight of the pharmaceutical composition.

Such compositions are prepared in accordance with acceptablepharmaceutical procedures, such as described in Remington'sPharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, MackPublishing Company, Easton, Pa. (1985), the entire disclosure of whichis herein incorporated by reference. Pharmaceutically acceptablecarriers are those that are compatible with the other ingredients in theformulation and biologically acceptable.

The compounds of this invention may be administered orally orparenterally, neat or in combination with conventional pharmaceuticalcarriers. Applicable solid carriers can include one or more substancesthat may also act as flavoring agents, lubricants, solubilizers,suspending agents, fillers, glidants, compression aids, binders ortablet-disintegrating agents or an encapsulating material. In powders,the carrier is a finely divided solid that is in admixture with thefinely divided active ingredient. In tablets, the active ingredient ismixed with a carrier having the necessary compression properties insuitable proportions and compacted in the shape and size desired. Thepowders and tablets preferably contain up to about 99% of the activeingredient. Suitable solid carriers include, for example, calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers may be used in preparing solutions, suspensions,emulsions, syrups, and elixirs. The active ingredient of this inventioncan be dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fat. The liquid carrier can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers, or osmo-regulators. Suitable examples of liquid carriersfor oral and parenteral administration include water (particularlycontaining additives as above, e.g. cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g. glycols) and their derivatives,and oils (e.g. fractionated coconut oil and arachis oil). For parenteraladministration, the carrier can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are used insterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions for parenteral administration, whichare sterile solutions or suspensions, can be administered by, forexample, intramuscular, intraperitoneal or subcutaneous injection.Sterile solutions can also be administered intravenously. Oraladministration may be either liquid or solid composition form.

Preferably the pharmaceutical composition is in unit dosage form, e.g.as tablets, capsules, powders, solutions, suspensions, emulsions,granules, or suppositories. In such form, the composition is sub-dividedin unit dose containing appropriate quantities of the active ingredient;the unit dosage forms can be packaged compositions, for example packetedpowders, vials, ampoules, prefilled syringes or sachets containingliquids. The unit dosage form can be, for example, a capsule or tabletitself, or it can be the appropriate number of any such compositions inpackage form.

In another embodiment of the present invention, the compounds useful inthe present invention may be administered to a mammal with one or moreother pharmaceutical active agents such as those agents being used totreat any other medical condition present in the mammal. Examples ofsuch pharmaceutical active agents include pain relieving agents,anti-angiogenic agents, anti-neoplastic agents, anti-diabetic agents,anti-infective agents, or gastrointestinal agents, or combinationsthereof.

The one or more other pharmaceutical active agents may be administeredin a therapeutically effective amount simultaneously (such asindividually at the same time, or together in a pharmaceuticalcomposition), and/or successively with one or more compounds of thepresent invention.

The term “combination therapy” refers to the administration of two ormore therapeutic agents or compounds to treat a therapeutic condition ordisorder described in the present disclosure, for example hot flush,sweating, thermoregulatory-related condition or disorder, or othercondition or disorder. Such administration includes use of each type oftherapeutic agent in a concurrent manner. In either case, the treatmentregimen will provide beneficial effects of the drug combination intreating the conditions or disorders described herein.

The route of administration may be any enteral or parenteral route whicheffectively transports the active compound of formula I, or apharmaceutically acceptable salt thereof, to the appropriate or desiredsite of action; such as oral, nasal, pulmonary, transdermal, such aspassive or iontophoretic delivery, or parenteral, e.g. rectal, depot,subcutaneous, intravenous, intraurethral, intramuscular, intrathecal,intra-articular, intranasal, ophthalmic solution or an ointment.Furthermore, the administration of compound of formula I, orpharmaceutically acceptable salt thereof, with other active ingredientsmay be separate, consecutive or simultaneous.

The present invention is further defined in the following Examples, inwhich all parts and percentages are by weight and degrees are Celsius,unless otherwise stated. It should be understood that these examples,while indicating preferred embodiments of the invention, are given byway of illustration only. From the above discussion and these examples,one skilled in the art can ascertain the essential characteristics ofthis invention, and without departing from the spirit and scope thereof,can make various changes and modifications of the invention to adapt itto various usages and conditions.

EXAMPLES Example 1, 2, and 34-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol

Step 1: 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.45 g, 1.7 mmol) was dissolved in tetrahydrofuran (20 mL)and triphenylphosphine (0.54 g, 2 mmol) was added followed by3-buten-1-ol (0.16 mL, 1.87 mmol) and diisopropyl azodicarboxylate (0.39g, 2 mmol). The mixture was stirred for 18 hours at 23° C. The mixturewas concentrated and purified via Isco chromatography (Redisep, silica,gradient 0-50% ethyl acetate in hexane) to afford 0.44 g of1-(but-3-enyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide.

HPLC purity 99.1% at 210-370 nm, 8.7 minutes; Xterra RP18, 3.5 u,150×4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium formate bufferpH=3.5/ACN+MeOH) for

10 minutes hold 4 minutes

Step 2:1-(but-3-enyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.44 g, 1.64 mmol) was dissolved in CH₂Cl₂ (10 mL) at 23°C. 3-chlorobenzoperoxoic acid (1.02 g, 3.9 mmol) was added and themixture allowed to stir for 18 h then filtered and concentrated. Theresidue was diluted with EtOAc and washed with 10% NaHCO₃ solution thenbrine. After drying with Na₂SO₄ the solution was concentrated then 300mg of the residue was dissolved in 10 mL of MeNH₂ solution (8M in EtOH).The solution was irradiated in a microwave cuvette at 100° C. for 3minutes. The reaction mixture was concentrated then loaded directly ontosilica gel and purified via Isco chromatography (Redisep, silica,gradient 0-10% 7M ammonia/MeOH solution in dichloromethane) to afford300 mg of racemic4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol.

HRMS: calculated for C17H15FN2O+H+, 366.1288; found (ESI, [M+H]+),366.1279

HPLC purity 100% at 210-370 nm, 6.9 minutes; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium formate bufferpH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes

Step 3: Approximately 300 mg of racemic4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-olwas dissolved in 4 mL of methanol. 200 μL of the resulting solution wasrepetitively injected onto the Supercritical Fluid Chromatographyinstrument, and the baseline resolved enantiomers were separatelycollected using the conditions described below. The chiral purity ofeach enantiomer was determined under the same Supercritical FluidChromatography conditions using a 250 mm×4.6 mm ID column at 2.0 mL/minflow rate using Chiralpak AS-H 5 Analytical Supercritical FluidChromatography (Berger Instruments, Inc. Newark, Del.). Both enantiomerswere found to be >99.9% enantiomerically pure.

-   SFC Instrument: Berger MultiGram Prep SFC (Berger Instruments, Inc.    Newark, Del.)-   Column: Chiralpak AS-H; 5 μm; 250 mm L×20 mm ID (Chiral    Technologies, Inc, Exton, Pa.)-   Column temperature: 35° C.-   SFC Modifier: 18% MeOHw 0.2% DMEA-   Flow rate: 50 mL/min-   Outlet Pressure: 100 bar-   Detector: UV at 220 nm.

Example 3A(S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol

Step 1: To a solution of N1-(2-fluorophenyl)benzene-1,2-diamine, 1, (1g, 5 mmol) in methanol (100 mL) was added the aldehyde (0.72 g, 5 mmol)followed by acetic acid (0.12 mL, 2 mmol) and sodium cyanoborohydride(3.15 g, 50 mmol). The reaction was stirred for 8 hour at 23° C. thenNaHCO₃ solution (50 mL) added. The mixture was extracted with EtOAC (3×)and the combined organic layers washed with brine, dried (Na₂SO₄) andconcentrated. The residue was purified via HPLC (SFC, 10% MeOH in CO₂,20×250 mm Kromasil CN) to afford 0.74 g (68%) of the desired product 2as a clear oil.

HPLC purity 99.4% at 210-370 nm, 10.5 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Step 2: To a solution of 2 (0.53 g, 1.6 mmol) in THF (20 mL) at 0° C.was added triethylamine (0.68 mL, 4.8 mmol) followed by thionyl chloride(0.17 ml, 2.4 mmol) dropwise. The reaction was allowed to stir for 0.5 hthen diluted with EtOAc and washed with water and brine. After dryingwith Na₂SO₄ the solution was concentrated then purified via Iscochromatography (Redisep, silica, gradient 0-50% EtOAc) to afford 0.56 g(93%) of 3 as a clear oil.

HRMS: calcd for C19H21FN2O3S+H+, 377.1330; found (ESI, [M+H]+), 377.1331

HPLC purity 53.4% (unstable) at 210-370 nm, 3.7 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff.Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.

Step 3: 3 (0.46 g, 1.22 mmol) was dissolved in acetonitrile/water (1:1,20 mL) at 0° C. Sodium Periodate (0.39 g, 1.8 mmol) was added followedby RuCl₃.(H₂O)_(x) (11 mg, catalytic) and the mixture was stirred for 1h then filtered through Celite. The mixture was diluted with EtOAc,washed with water and brine then dried with Na₂SO₄ and concentrated. Theresidue was purified via Isco chromatography (Redisep, silica, gradient0-50% EtOAc) to afford 0.45 g (94%) of 4 as a clear oil.

HRMS: calcd for C19H21FN2O4S+H+, 393.128; found (ESI, [M+H]+), 393.1279

HPLC purity 100% at 210-370 nm, 10 min.; Xterra RP18, 3.5 u, 150×4.6 mmcolumn, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for10 min, hold 4 min.

Step 4: 4 (0.425 g, 1.1 mmol) was dissolved in THF (20 mL) at 23° C. 2NHCl (10 mL) was added dropwise and the mixture was stirred for 4 h thena saturated solution of NaHCO₃ added slowly. The mixture was extractedwith CH₂Cl₂ (4×) and the combined layers washed with brine, dried withNa₂SO₄ and concentrated. The residue was purified via Iscochromatography (Redisep, silica, gradient 0-100% EtOAc) to afford 0.325g (85%) of 5 as a clear oil.

HRMS: calcd for C16H17FN2O4S+H+, 353.0966; found (ESI, [M+H]+),353.0969.

HPLC purity 100% at 210-370 nm, 7.9 min.; Xterra RP18, 3.5 u, 150×4.6 mmcolumn, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for10 min, hold 4 min.

Step 5: 5 (0.29 g, 0.82 mmol) was dissolved in CH₂Cl₂ (15 mL) at 0° C.Triethylamine (0.14 mL, 0.99 mmol) was added followed byp-toluenesulfonyl chloride (0.17 g, 0.9 mmol). The mixture was stirredat 0° C. for 1 hour then allowed to warm to 23° C. over 6 h. Thereaction was washed with water, a 10% HCl solution, NaHCO₃ and brine.After drying with Na₂SO₄ and concentration, the residue was purified viaIsco chromatography (Redisep, silica, gradient 0-60% EtOAc) to afford0.229 g (55%) of 6 as a clear oil.

HRMS: calcd for C23H23FN2O6S2+H+, 507.1054; found (ESI, [M+H]+),507.1056.

HPLC purity 98.5% at 210-370 nm, 10.1 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Step 6: 6 (0.2 g, 0.4 mmol) was dissolved in MeOH/THF (1:1, 10 mL) at23° C. Potassium carbonate (0.06 g, 0.43 mmol) was added and thereaction was stirred at 23° C. for 18 hour then diluted with CH₂Cl₂ (20mL). The reaction was washed with water, dried over Na₂SO₄, concentratedand purified via Isco chromatography (Redisep, silica, gradient 0-50%EtOAc) to afford 0.08 g (60%) of 7 as a clear oil.

HRMS: calcd for C16H15FN2O3S+H+, 335.086; found (ESI, [M+H]+), 335.0863.

HPLC purity 98.4% at 210-370 nm, 9.1 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Step 7: 7 (0.08 g, 0.23 mmol) was dissolved in MeNH₂ solution (8M inEtOH, 10 mL). The solution was heated to 60° C. for 1 hour. The reactionmixture was cooled and concentrated then loaded directly onto silica geland purified via Isco chromatography (Redisep, silica, gradient 0-100%of 10% 7M ammonia in MeOH/dichloromethane) to afford 0.08 g (95%) of 8as a foamy oil. This was dissolved in CH₂Cl₂ (5 mL) and HCl added (4N indioxane, 0.11 mL). After stirring for 30 minutes at 23° C. the mixturewas concentrated then redissolved in CH₂Cl₂ (2 mL) and tert-butyl methylether added until the solution was almost cloudy. The solution wasallowed to sit for several hours at 23° C. until crystals had formed.These were collected by filtration and dried under vacuo.

HRMS: calcd for C16H15FN2O3S+H+, 366.1282; found (ESI, [M+H]+),366.1287.

HPLC purity 100% at 210-370 nm, 6.8 min.; Xterra RP18, 3.5 u, 150×4.6 mmcolumn, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for10 min, hold 4 min.

Example 3B Alternative Asymmetric route to(S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol

Step 1: 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.5 g, 1.9 mmol) was dissolved in acetone (5 mL) andpotassium carbonate (0.52 g, 3.8 mmol) was added followed byS(−)-4-bromo-1,2-epoxybutane (0.57 g, 3.8 mmol). The mixture was stirredfor 18 hours at 50° C. in a sealed vial then diluted with EtOAc (100 mL)and washed with water (2×), brine then dried (Na₂SO₄). Afterconcentration the residue was dissolved in 10 mL of MeNH₂ solution (8Min EtOH). The solution was irradiated in a microwave cuvette at 10° C.for 3 minutes. The reaction mixture was concentrated then loadeddirectly onto silica gel and purified via Isco chromatography (Redisep,silica, gradient 0-100% of 10% 7M ammonia in MeOH/dichloromethane) toafford 387 mg of(S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol.

HRMS: calcd for C17H20FN3O3S+H+, 366.1288; found (ESI, [M+H]+), 366.1279

HPLC purity 100% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5 u, 150×4.6 mmcolumn, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for10 min, hold 4 min.

Example 41-amino-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol

Step 1:1-(but-3-enyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.44 g, 1.64 mmol) was dissolved in CH₂Cl₂ (10 mL) at 23°C. 3-chlorobenzoperoxoic acid (1.02 g, 3.9 mmol) was added and themixture allowed to stir for 18 h then filtered and concentrated. Theresidue was diluted with EtOAc and washed with 10% NaHCO₃ solution thenbrine. After drying with Na₂SO₄ the solution was concentrated then 50 mgof the residue was dissolved in 2 mL of NH₃ solution (7M in MeOH). Thesolution was irradiated in a microwave cuvette at 100° C. for 3 minutes.The reaction mixture was concentrated then loaded directly onto silicagel and purified via Isco chromatography (Redisep, silica, gradient0-10% 7M ammonia/MeOH solution in dichloromethane) to afford 20 mg of1-amino-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol.

HRMS: calculated for C17H15FN2O+H+, 352.1131; found (ESI, [M+H]+),352.1129

HPLC purity 89.4% at 210-370 nm, 6.8 minutes; Xterra RP18, 3.5 u,150×4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium formate bufferpH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes

Example 53-fluoro-4-{3-[(3S)-3-hydroxy-4-(methylamino)butyl]-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl}phenolhydrochloride

Step 1: In an analogous manner to example 3B, (2S)-4-[3-(2-fluoro,4-((2-(trimethylsilyl)ethoxy)methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-olwas prepared from1-(4-bromobutyl)-3-(2-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide, S(−)-4-bromo-1,2-epoxybutane and methylamine (33% inethanol).

Step 3: The product from Step 1 was dissolved in 9:1 ether:methanol and2N HCl in ether added. After allowing to stand overnight a solid formedwhich was remover by filtration to afford3-fluoro-4-{3-[(3S)-3-hydroxy-4-(methylamino)butyl]-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl}phenolhydrochloride.

MS (ES) m/z 382.1; HPLC purity 95.5% at 210-370 nm, 6.4 min.; XterraRP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min. HRMS: calcd forC17H20FN3O4S+H+, 382.12313; found (ESI, [M+H]+ Obs'd), 382.1233.

Example 65-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)pentan-2-ol

Example 6 was prepared using1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and4-penten-1-ol analogous to the conditions used in example 1.

HRMS: calcd for C18H22FN3O3S+H+, 380.1439; found (ESI, [M+H]+), 380.1439

HPLC purity 97.5% at 210-370 nm, 6.8 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Example 7(2S)-1-amino-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol

Example 7 was prepared using1-(2-fluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide and ammonia analogous to the conditions used in step 2 ofexample 1.

HRMS: calcd for C16H18FN3O3S+H+, 352.1126; found (ESI, [M+H]+), 352.1126

HPLC purity 78.8% at 210-370 nm, 10.5 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Example 8(2S)-5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)pentan-2-ol

Example 8 was prepared using1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and4-penten-1-ol analogous to the conditions used in example 1.

HRMS: calcd for C18H22FN3O3S+H+, 380.1439; found (ESI, [M+H]+), 380.1444

HPLC purity 91.1% at 210-370 nm, 7.9 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Example 9(2R)-5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)pentan-2-ol

Example 9 was prepared using1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and4-penten-1-ol analogous to the conditions used in example 1

HRMS: calcd for C18H22FN3O3S+H+, 380.1439; found (ESI, [M+H]+), 380.1446

HPLC purity 94.7% at 210-370 nm, 7.9 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Example 104-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(ethylamino)butan-2-ol

Example 10 was prepared using1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide and ethylamine analogous to the conditions used in step 2 ofexample 1.

HRMS: calcd for C18H23N3O3S+H+,

HPLC purity 100% at 210-370 nm, 7.2 min.; Xterra RP18, 3.5 u, 150×4.6 mmcolumn, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for10 min, hold 4 min.

Example 111-(dimethylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol

Example 11 was prepared using1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide and dimethylamine analogous to the conditions used in step 2of example 1.

HRMS: calcd for C₁₈H₂₃N₃O₃S+H+, 362.1533; found (ESI, [M+H]+), 362.1536

HPLC purity 99.3% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Example 124-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(isopropylamino)butan-2-ol

Example 12 was prepared using1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide and isopropylamine analogous to the conditions used in step2 of example 1.

HRMS: calcd for C19H25N3O3S+H+, 376.1689; found (ESI, [M+H]+), 376.1695

HPLC purity 97.3% at 210-370 nm, 7.4 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Example 131-(cycloprolylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol

Example 13 was prepared using1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide and cyclopropylamine analogous to the conditions used instep 2 of example 1.

HRMS: calcd for C19H23N3O3S+H+, 374.1533; found (ESI, [M+H]+), 374.1537

HPLC purity 100% at 210-370 nm, 7.3 min.; Xterra RP18, 3.5 u, 150×4.6 mmcolumn, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for10 min, hold 4 min.

Example 141-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol

Example 14 was prepared using1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide and t-butylamine analogous to the conditions used in step 2of example 1.

HRMS: calcd for C20H27N3O₃S+H+, 390.1846; found (ESI, [M+H]+), 390.1850

HPLC purity 100% at 210-370 nm, 7.6 min.; Xterra RP18, 3.5 u, 150×4.6 mmcolumn, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for10 min, hold 4 min.

Example 154-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylamino)butan-2-ol

Example 15 was prepared using1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide and methylamine analogous to the conditions used in step 2of example 1.

HRMS: calcd for C17H21N3O3S+H+, 348.1376; found (ESI, [M+H]+), 348.1381

HPLC purity 99.7% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Example 16(2R)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylamino)butan-2-ol

Example 16 was prepared using1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide and methylamine analogous to the conditions used in step 2of example 1.

HRMS: calcd for C17H21N3O3S+H+, 348.1376; found (ESI, [M+H]+), 348.1381

HPLC purity 97.5% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Example 17(2S)-1-(dimethylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol

Example 17 was prepared using1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide and methylamine analogous to the conditions used in step 2of example 1.

HRMS: calcd for C18H23N3O3S+H+, 362.1533; found (ESI, [M+H]+), 362.1537

HPLC purity 100% at 210-370 nm, 7.0 min.; Xterra RP18, 3.5 u, 150×4.6 mmcolumn, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for10 min, hold 4 min.

Example 18(2R)-1-(dimethylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol

Example 18 was prepared using1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide and dimethylamine analogous to the conditions used in step 2of example 1.

HRMS: calcd for C₁₈H₂₃N₃O₃S+H+, 362.1533; found (ESI, [M+H]+), 362.1537

HPLC purity 100% at 210-370 nm, 7.0 min.; Xterra RP18, 3.5 u, 150×4.6 mmcolumn, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for10 min, hold 4 min.

Example 19(2S)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(isopropylamino)butan-2-ol

Example 19 was prepared using1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide and isopropylamine analogous to the conditions used in step2 of example 1.

HRMS: calcd for C19H25N3O3S+H+, 376.1689; found (ESI, [M+H]+), 376.1697

HPLC purity 100% at 210-370 nm, 7.3 min.; Xterra RP18, 3.5 u, 150×4.6 mmcolumn, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for10 min, hold 4 min.

Example 20(2R)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(isopropylamino)butan-2-ol

Example 20 was prepared using1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide and isopropylamine analogous to the conditions used in step2 of example 1.

HRMS: calcd for C19H25N3O3S+H+, 376.1689; found (ESI, [M+H]+), 376.1697

HPLC purity 98.7% at 210-370 nm, 7.3 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Example 21(2S)-1-(cycloprolylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol

Example 21 was prepared using1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide and cyclopropylamine analogous to the conditions used instep 2 of example 1.

HRMS: calcd for C19H23N3O3S+H+, 374.1533; found (ESI, [M+H]+), 374.1536

HPLC purity 98.0% at 210-370 nm, 7.3 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Example 22(2S)-1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol

Example 22 was prepared using1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide and t-butylamine analogous to the conditions used in step 2of example 1.

HRMS: calcd for C20H27N3O3S+H+, 390.1846; found (ESI, [M+H]+), 390.1854

HPLC purity 100% at 210-370 nm, 7.6 min.; Xterra RP18, 3.5 u, 150×4.6 mmcolumn, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for10 min, hold 4 min.

Example 23(2R)-1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol

Example 23 was prepared using1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide and t-butylamine analogous to the conditions used in step 2of example 1.

HRMS: calcd for C20H27N3O3S+H+, 390.1846; found (ESI, [M+H]+), 390.1853

HPLC purity 100% at 210-370 nm, 7.6 min.; Xterra RP18, 3.5 u, 150×4.6 mmcolumn, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for10 min, hold 4 min.

Example 24(2S)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(ethylamino)butan-2-ol

Example 24 was prepared using1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide and ethylamine analogous to the conditions used in step 2 ofexample 1.

HRMS: calcd for C18H23N3O3S+H+, 362.1533; found (ESI, [M+H]+), 362.1540

HPLC purity 99.4% at 210-370 nm, 7.1 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Example 25(2R)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(ethylamino)butan-2-ol

Example 25 was prepared using1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide and ethylamine analogous to the conditions used in step 2 ofexample 1.

HRMS: calcd for C18H23N3O3S+H+, 362.1533; found (ESI, [M+H]+), 362.1539

HPLC purity 99.3% at 210-370 nm, 7.1 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Example 26(2S)-1-(cycloprolylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol

Example 26 was prepared using1-(2-fluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide and cyclopropylamine analogous to the conditions used instep 2 of example 1.

HRMS: calcd for C19H22FN3O3S+H+, 392.1439; found (ESI, [M+H]+), 392.1441

HPLC purity 95.4% at 210-370 nm, 9.3 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Example 27(2S)-1-(cyclopropylamino)-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol

Example 27 was prepared using1-(2-methylphenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide and cyclopropylamine analogous to the conditions used instep 2 of example 1.

HRMS: calcd for C20H25N3O3S+H+, 388.1689; found (ESI, [M+H]+), 388.1690

HPLC purity 100% at 210-370 nm, 9.9 min.; Xterra RP18, 3.5 u, 150×4.6 mmcolumn, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for10 min, hold 4 min.

Example 28(2S)-1-(cyclopropylamino)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol

Example 28 was prepared using1-(2,4-difluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide and cyclopropylamine analogous to the conditions used instep 2 of example 1.

HRMS: calcd for C19H21F2N3O3S+H+, 410.1345; found (ESI, [M+H]+),410.1344

HPLC purity 100% at 210-370 nm, 9.5 min.; Xterra RP18, 3.5 u, 150×4.6 mmcolumn, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for10 min, hold 4 min.

Example 29(2S)-1-(cycloprolylamino)-4-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol

Example 29 was prepared using1-(2,5-difluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide and cyclopropylamine analogous to the conditions used instep 2 of example 1.

HRMS: calcd for C19H21F2N3O3S+H+, 410.1345; found (ESI, [M+H]+),410.1347

HPLC purity 96.0% at 210-370 nm, 9.5 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Example 30(2S)-1-(cyclopropylamino)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol

Example 30 was prepared using1-(2,6-difluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide and cyclopropylamine analogous to the conditions used instep 2 of example 1.

HRMS: calcd for C19H21F2N3O3S+H+, 410.1345; found (ESI, [M+H]+),410.1345

HPLC purity 100% at 210-370 nm, 9.1 min.; Xterra RP18, 3.5 u, 150×4.6 mmcolumn, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for10 min, hold 4 min.

Example 31(2S)-1-(cycloprolylamino)-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol

Example 31 was prepared using1-(3-methoxyphenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide and cyclopropylamine analogous to the conditions used instep 2 of example 1.

HRMS: calcd for C20H25N3O4S+H+, 404.1639; found (ESI, [M+H]+), 404.1641

HPLC purity 98.1% at 210-370 nm, 7.6 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Example 32(2S)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylamino)butan-2-ol

This compound was prepared using1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide,S(−)-4-bromo-1,2-epoxybutane and methylamine analogous to the conditionsused in example 3B.

HRMS: HRMS: calcd for C17H21N3O3S+H+, 348.1376; found (ESI, [M+H]+),348.1384.

HPLC purity 97.8% at 210-370 nm, 6.7 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Example 33(2S)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol

This compound was prepared using1-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide,S(−)-4-bromo-1,2-epoxybutane and methylamine analogous to the conditionsused in example 3B.

HRMS: HRMS: calcd for C17H19F2N3O3S+H+, 384.1194; found (ESI, [M+H]+),384.1188.

HPLC purity 95.9% at 210-370 nm, 6.7 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Example 34(2S)-4-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol

This compound was prepared using1-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide,S(−)-4-bromo-1,2-epoxybutane and methylamine analogous to the conditionsused in example 3B.

HRMS: HRMS: calcd for C17H19F2N3O3S+H+, 384.1192; found (ESI, [M+H]+),384.1188.

HPLC purity 80.3% at 210-370 nm, 6.7 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Example 35(2S)-4-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol

This compound was prepared using1-(2,5-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide,S(−)-4-bromo-1,2-epoxybutane and methylamine analogous to the conditionsused in example 3B.

HRMS: C17H19F2N3O3S+H+, (ESI, [M+H]+), 378.1485

HPLC purity 100% at 210-370 nm, 7.3 min.; Xterra RP18, 3.5 u, 150×4.6 mmcolumn, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for10 min, hold 4 min.

Example 36(2S)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol

This compound was prepared using1-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide,S(−)-4-bromo-1,2-epoxybutane and methylamine analogous to the conditionsused in example 3B.

HRMS: calcd for C17H19F2N3O3S+H+, 353.0766; found (ESI, [M+H]+,353.0768.

HPLC purity 98.0% at 210-370 nm, 9.3 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Example 37(2S)-4-[3-(4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol

This compound was prepared using1-(4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide,S(−)-4-bromo-1,2-epoxybutane and methylamine analogous to the conditionsused in example 3B.

HRMS: calcd for C17H19FN3O3S+H+, 366.1282; found (ESI, [M+H]+, 366.1287.

HPLC purity 84.4% at 210-370 nm, 9.3 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Example 38(2S)-1-(methylamino)-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol

This compound was prepared using1-(2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide,S(−)-4-bromo-1,2-epoxybutane and methylamine analogous to the conditionsused in example 3B.

HRMS: calcd for C18H23N3O3S+H+, 362.1533; found (ESI, [M+H]+, 362.1538

HPLC purity 78.6% at 210-370 nm, 7.4 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Example 39(2S)-4-[3-(2-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol

This compound was prepared using1-(2-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide,S(−)-4-bromo-1,2-epoxybutane and methylamine analogous to the conditionsused in example 3B.

HRMS: calcd for C17H20ClN₃O3S+H+, 382.0987; found (ESI, [M+H]+, 382.0993

HPLC purity 77.4% at 210-370 nm, 7.4 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Example 40(S)-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol

This compound was prepared using1-(3-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide,S(−)-4-bromo-1,2-epoxybutane and methylamine analogous to the conditionsused in example 3B.

HRMS: calcd for C18H23N3O23S+H+, 378.1482; found (ESI, [M+H]+), 378.1484

HPLC purity 100% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5 u, 150×4.6 mmcolumn, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for10 min, hold 4 min.

Example 41(R)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol

Step 1: 1-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.15 g, 0.5 mmol) was dissolved in acetone (5 mL) andpotassium carbonate (0.14 g, 1.0 mmol) was added followed by(R)-2-(oxiran-2-yl)ethyl 4-tosylate (0.24 g, 1.0 mmol). The mixture wasstirred for 18 hours at 50° C. in a sealed vial then diluted with EtOAc(100 mL) and washed with water (2×), brine then dried (Na₂SO₄). Afterconcentration the residue was dissolved in 10 mL of MeNH₂ solution (8Min EtOH). The solution was irradiated in a microwave cuvette at 100° C.for 3 minutes. The reaction mixture was concentrated then loadeddirectly onto silica gel and purified via Isco chromatography (Redisep,silica, gradient 0-100% of 10% 7M ammonia in MeOH/dichloromethane) toafford 59 mg of(R)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol.

HRMS: calcd for C17H19F2N3O3S+H+, 384.1188; found (ESI, [M+H]+),384.1191

HPLC purity 79.9% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Example 42(R)-4-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol

This compound was prepared using1-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide,(R)-2-(oxiran-2-yl)ethyl 4-tosylate and methylamine analogous to theconditions used in example 41.

HRMS: calcd for C17H19F2N3O3S+H+, 384.1188; found (ESI, [M+H]+),384.1190

HPLC purity 93.6% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Example 43(R)-4-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol

This compound was prepared using1-(2,5-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide,(R)-2-(oxiran-2-yl)ethyl 4-tosylate and methylamine analogous to theconditions used in example 41.

HRMS: calcd for C17H19F2N3O3S+H+, 384.1188; found (ESI, [M+H]+),384.1189

HPLC purity 92.8% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Example 44(R)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol

This compound was prepared using1-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide,(R)-2-(oxiran-2-yl)ethyl 4-tosylate and methylamine analogous to theconditions used in example 41.

HRMS: calcd for C17H19F2N3O3S+H+, 384.1188; found (ESI, [M+H]+),384.1193

HPLC purity 86.6% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Example 45(R)-4-[3-(4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol

This compound was prepared using1-(4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide,(R)-2-(oxiran-2-yl)ethyl 4-tosylate and methylamine analogous to theconditions used in example 41.

HRMS: calcd for C17H20FN3O3S+H+, 366.1282; found (ESI, [M+H]+), 366.1291

HPLC purity 94.2% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Example 46(2R)-1-(methylamino)-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol

This compound was prepared using1-(2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide,(R)-2-(oxiran-2-yl)ethyl 4-tosylate and methylamine analogous to theconditions used in example 41.

HRMS: calcd for C18H23N3O3S+H+, 362.1533; found (ESI, [M+H]+), 362.1538

HPLC purity 94.5% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Example 47(R)-4-[3-(2-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol

This compound was prepared using1-(2-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide,(R)-2-(oxiran-2-yl)ethyl 4-tosylate and methylamine analogous to theconditions used in example 41.

HRMS: calcd for C17H20ClN3O3S+H+, 382.0987; found (ESI, [M+H]+), 382.099

HPLC purity 94.1% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Example 48(R)-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol

This compound was prepared using1-(3-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide,(R)-2-(oxiran-2-yl)ethyl 4-tosylate and methylamine analogous to theconditions used in example 41.

HRMS: calcd for C18H23N3O23S+H+, 378.1482; found (ESI, [M+H]+), 378.149

HPLC purity 95.3% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5 u, 150×4.6mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)for 10 min, hold 4 min.

Example 49(2S)-1-(cyclobutylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-olhydrochloride

Step 1: In an analogous manner to Example 3B,1-(2-fluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.1 g, 0.3 mmol) was treated with cyclobutylamine (1 mL, 12mmol) in methanol to give(2S)-1-(cyclobutylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-olwhich was treated with 1N hydrochloric acid in ether to give itshydrochloride salt as a white solid (0.59 g, 44%). HRMS: calcd forC₂₀H₂₄FN₃O₃S+H⁺, 406.15952; found (ESI, [M+H]⁺ Obs'd), 406.1591. HPLCretention time: 7.5 min.

Example 50(2S)-1-(cyclopentylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-olhydrochloride

Step 1: In an analogous manner to Example 3B,1-(2-fluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.1 g, 0.3 mmol) was treated with cyclopentylamine (1.2 mL,12 mmol) in methanol to give(2S)-1-(cyclopentylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-olwhich was treated with 1N hydrochloric acid in ether to give itshydrochloride salt as a white solid (0.67 g, 49%). HRMS: calcd forC₂₁H₂₆FN₃O₃S+H⁺, 420.17517; found (ESI, [M+H]⁺ Obs'd), 420.1746. HPLCretention time: 7.8 min.

Example 51(2S)-1-(cyclohexylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-olhydrochloride

Step 1: In an analogous manner to Example 3B,1-(2-fluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.1 g, 0.3 mmol) was treated with cyclohexylamine (1.4 mL,12 mmol) in methanol to give(2S)-1-(cyclohexylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-olwhich was treated with 1N hydrochloric acid in ether to givehydrochloride salt as a white solid (0.84 g, 59%). HRMS: calcd forC₂₂H₂₈FN₃O₃S+H⁺, 434.19082; found (ESI, [M+H]⁺ Obs'd), 434.1902. HPLCretention time: 8.1 min.

Example 52(2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(isopropylamino)butan-2-olhydrochloride

Step 1: In an analogous manner to Example 3B,1-(2-fluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.1 g, 0.3 mmol) was treated with cyclohexylamine (1.4 mL,12 mmol) in methanol to give(2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(isopropylamino)butan-2-olwhich was treated with 1N hydrochloric acid in ether to give itshydrochloride salt as a white solid (0.74 g, 57%). HRMS: calcd forC₁₉H₂₄FN₃O₃S+H⁺, 394.15952; found (ESI, [M+H]⁺ Obs'd), 394.1590. HPLCretention time: 7.3 min.

Example 53(2S)-1-(ethylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-olhydrochloride

Step 1: In an analogous manner to Example 3B,1-(2-fluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.1 g, 0.3 mmol) was treated with 30-40% ethylamine inmethanol to give(2S)-1-(ethylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-olwhich was treated with 1N hydrochloric acid in ether to give a whitehydrochloride salt (0.74 g, 59%). MS (ES) m/z 379.9 ([M+H]⁺). HPLCretention time: 7.0 min.

hNET Assay Procedure Protocol A: Inhibition of [³H] NE Uptake intoCloned Human NE Transporters (MDCK Cells) (“hNET Uptake”)

The hNET uptake assay procedure was used to screen for compounds thatinhibit the reuptake of norepinephrine and to determine IC₅₀ values forcompounds identified as hNET reuptake inhibitors.

Materials and Methods: Cell Line and Culture Reagents:

[³H] NE uptake studies were performed using MDCK cells stably expressinghuman norepinephrine transporter (hNET) (See Pacholczyk T, Blakely R Dand Amara S G (1991) Expression cloning of a cocaine- andantidepressant-sensitive human noradrenaline transporter. Nature.350:350-354) cultured in growth medium containing high glucose DMEM(Gibco, Cat. No. 11995), 10% FBS (dialyzed, heat-inactivated, USBio-Technologies, Lot FBD1129HI) and 500 μg/ml G418 (Gibco, Cat. No.10131). Cells were seeded at 300,000/T75 flask, and split twice weekly.

Norepinephrine Uptake Assays:

All uptake experiments were performed in 96-well plates (Falcon Optilux,cat #353947) in a total volume of 250 μl/well. MDCK cells were plated at50,000 cells/well. At the time of the assay, the media was removed, and200 μl assay buffer (25 mM Hepes, 120 mM NaCl, 5 mM KCl, 2.5 mM CaCl₂,1.2 mM MgSO₄.7H₂O, 2 mg/ml glucose, 0.2 mg/ml ascorbic acid, 1 μMpargyline, pH 7.4) was added to each well. 25 μl of each test compoundwas subsequently added to plates in triplicate and incubated at 37° C.for 5 minutes. All test compounds were dissolved in 100% DMSO anddiluted in 4% DMSO/H₂O, and assayed using a 7-point dose response curve(1 nM-10 μM). Next, 25 μl of [³H] NE (74.9 Ci/mmol, Perkin Elmer,Boston, Mass.) was added to all wells and incubated at 37° C. for anadditional 5 minutes. Non-specific uptake was defined by 20 μMdesipramine. The final concentrations of [³H] NE was 16 nM,respectively. The reaction was terminated by aspiration and washed withice cold 50 mM Tris (pH 7.4). The plates were left to air dry forroughly 30 min, and MDCK cells were lysed by the addition of 25 μl of0.25 M NaOH. 100 μl of Microscint-20 were added to each well (Packard,Perkin Elmer, Boston, Mass.), and the plates were counted using aTopCount (Perkin Elmer, Downer's Grove, Ill.) liquid scintillationcounter.

Analysis of Results:

% Inhibition of uptake=((mean cpm control wells−each cpm drugwell)/(mean cpm control wells−non-specific wells)×100.

IC₅₀ values were calculated using a Prism® nonlinear regression programwhere % inhibition is plotted versus concentration of inhibitor.

See: Pacholczyk T, Blakely R D and Amara S G (1991) Expression cloningof a cocaine- and antidepressant-sensitive human noradrenalinetransporter. Nature. 350:350-354.

See also: Ramamoorthy J D, Ramamoorthy S, Papapetropoulos A, Catravas JD, Leibach F H and Ganaphthy V (1995) Cyclic AMP-independentup-regulation of the human serotonin transporter by staurosporine inchoriocarcinoma cells. Journal of Biological Chemistry. 270:17189-17195,the contents of which is hereby incorporated by reference.

hNET Assay Procedure Protocol B: Cell Based Norepinephrine (NE) ReuptakeAssay Using the Recombinant Human Norepinephrine Transporter (hNET)(“hNET Uptake”)

The hNET uptake assay procedure was used to screen for compounds thatinhibit the reuptake of norepinephrine and to determine IC₅₀ values forcompounds identified as hNET reuptake inhibitors.

Materials and Methods: Compounds:

For screening, hydrochloride salts of compounds were dissolved insolution and 25 μl aliquots of compound solution at a 1 μM or 10 μMfinal concentration delivered directly to cells. For IC₅₀determinations, stock compounds were prepared at 10 mM from powder. Thestock solution was diluted according to compound testing range.Typically, the compound testing range was from 6 nM to 6 μM by half logdilutions. On the day of assay, 25 μl of compound solution at thespecified concentrations was added to the plates containing cells. ADMSO stock of desipramine was prepared at 10 mM in DMSO and diluted fora final concentration of 20 μM to determine the non-specific reuptake.The radioligand in this assay is ³H-norepinephrine (NE) (PerkinElmer;NET678; 40-80 Ci/mmol) was delivered at approximately 16 nM finalconcentration for both single point testing and compound IC₅₀determinations.

Tissue Culture Conditions:

MDCK-Net6 cells, stably transfected with human hNET (See Pacholczyk T,Blakely R D and Amara S G (1991) Expression cloning of a cocaine- andantidepressant-sensitive human noradrenaline transporter. Nature.350:350-354) was maintained in growth media [high glucose DMEM (GibcoCat. 11995), 10% FBS (dialyzed, heat-inactivated, Sigma, dialysed, heatinactivated, Lot# K₀₉₂₂ or equivalent) 1×Pen/Strep, and 500 μg/ml G418(Gibco Cat. 10131)]. Cells were plated at 300,000/T75 flask and cellswere split twice weekly.

Functional Reuptake Assay:

Cells were plated at 3,000 cells/well on day 1 in BD Falcon Microtest96-well sterile cell culture plates, Optilux White/Clear Bottom TC plate(VWR; # 62406-466 or equivalent) in growth media and maintained in acell incubator (37° C., 5% CO₂). On Day 2, cells were removed from thecell incubator and the growth media is replaced by 200 μl of assaybuffer (25 mm HEPES 120 mM NaCL; 5 mM KCl; 2.5 mM CaCl₂; 1.2 mM MgSO₄; 2mg/ml glucose (pH 7.4, 37° C.)) containing 0.2 mg/ml ascorbic acid and 1μM parglyine. For screening, 25 μl of compound in 4% DMSO is addeddirectly to each well and the plate is incubated for 5 min (37° C.). Toinitiate the norepinephrine reuptake, 16 nM (final concentration) of ³Hnorepinephrine (specific activity; 40-80 Ci/mmol) in assay buffer wasdelivered in 25 μl aliquots to each well, and the plates were incubatedfor 5 min at 37° C. The reaction was aspirated from the plate and thecells washed with 250 μl of 50 mM Tris Buffer (4° C.). The plates wereleft to dry for 1 hour. The cells were lysed using 0.25 M NaOH solutionthen placed on a shake table and vigorously shaken for 10 min. Aftercell lysis, 100 μl of Microscint 20 (PerkinElmer; #87-051101) was addedto the plates and the plates were sealed with film tape and replaced onthe shake table for a minimum of 10 min. The plates were counted in aTopCount counter (PerkinElmer).

Analysis of Results:

For screening single point determinations, each compound plate containedat least 3 control wells (maximum NE reuptake determinant) and 3non-specific wells determined by adding 20 μM of desipramine (minimum NEreuptake determinant). Determination of active compounds were calculatedusing a Microsoft Excel spread sheet applying the following formula:

% inhibition=[1−((mean cpm test compound wells−mean cpm non-specificwells)/(mean cpm control wells−mean cpm non-specific wells))]×100

For IC₅₀ determination, raw cpm values were generated in a data filefrom the TopCount counter. The data was organized Microsoft Excel andtransferred into PRIZM graphing and statistical program, whichcalculated the estimated IC₅₀ value. Calculation of IC₅₀ values was madeusing non-linear regression analysis with a sigmoidal dose response withvariable slope. The statistical program used wells containing ³Hnorepinephrine only as the maximal NE reuptake determinant and wellscontaining ³H norepinephrine plus 20 μM desipramine as the minimal NEreuptake determinant (non-specific determinant). Estimation of the IC₅₀value is completed on a log scale and the line is fit between themaximal and minimal NE reuptake values. In the event that the highesttest concentration does not exceed 50% reuptake inhibition, data will bereported as percent maximal NE reuptake at the highest concentrationtested.

See: Pacholczyk, T., Blakely, R. D., and Amara, S. G. (1991) Expressioncloning of a cocaine- and antidepressant-sensitive human noradrenalinetransporter. Nature, 350, 350-354, the contents of which is herebyincorporated by reference.

Results are shown in the following table:

NE uptake (Protocol B) Example IC₅₀ (nM)  1 7.3  2 2.68  3 1.35   3A  3B  4 8.73  5 4  6 186  7 32  8 109  9 465 10 196 11 481 12 2255 13 914 853 15 2 16 3 17 252 18 278 19 2294 20 1158 21 6 22 3243 23 765 24148 25 193 26 13 27 358 28 214 29 34 30 13 31 292 32 4 33 4 34 43 35 336 18 37 146 38 64 39 28 40 25 41 9 42 394 43 10 44 100 45 328 46 294 4761 48 143 49 415 50 3833 51 5019 52 2118 53 104

Rat Liver Microsomal Stability Assay:

DMSO stock solutions of test compounds were prepared at 0.5 mMconcentration. Diluted solutions of test compounds were prepared byadding 50 uL of each DMSO stock solution to 200 uL of acetonitrile tomake 0.1 mM solutions in 20% DMSO/80% acetonitrile. Rat liver microsomalsolution was prepared by adding 1.582 mL of concentrated rat livermicrosomes (20 mg/mL protein concentration) to 48.291 mL of pre-warmed(to 37° C.) 0.1M potassium phosphate buffer (pH 7.4) containing 127 uLof 0.5 M EDTA to make a 0.6329 mg/mL (protein) microsomal solution. 11.2uL of each test compound diluted solution was each added directly to 885uL of rat liver microsomal solution (allowing direct binding of drugs tomicrosomal proteins and lipids to minimize precipitation andnon-specific binding to the plasticware). This solution was mixed and180 uL was transferred to “Time 0” and “Time 15 min” plates (each induplicate wells). For the Time 15 min plate, NADPH regenerating agent(45 uL) was added to each well to initiate the reaction, the plate wasincubated at 37° C. for 15 min, followed by quenching of the reaction byadding 450 uL of cold acetonitrile to each well. For the Time 0 plate,450 uL of cold acetonitrile was added to each well, followed by additionof NADPH regenerating agent (45 uL) and no incubation. All of the plateswere centrifuged at 3000 rpm for 15 min and the supernatants weretransferred to other well plates for analysis by LC-MS.

Dopamine Transporter (hDAT) Membrane Binding Assay

The method for this radioligand binding assay was modified from themethods supplied with hDAT membranes (catalog number RBHDATM; PerkinElmer Life Analytical Sciences), and those modifications are listedwithin this method section. Frozen membrane samples from a cell linethat expresses hDAT were diluted to 7.5 ml in binding buffer (50 mMTris-HCl; pH 7.4, 100 mM NaCl), homogenized with a tissue-tearer(Polytron PT 120° C., Kinematica AG) and delivered at a volume of 75 μlto each well of a polypropylene 96-well plate. The binding reaction wasrun in polypropylene 96-well plates (Costar General Assay Plate, Cat.No. 3359; Lid, Cat. No. 3930). A stock solution of mazindol was preparedin DMSO (10 mM) and delivered to triplicate wells containing membranefor a final test concentration of 10 uM. Mazindol is a DA transporterinhibitor with a 50% inhibitory concentration (IC₅₀) value of 18.0±6.0nM in the present assays. Data from wells containing mazindol (10 uM)were used to define non-specific (NSB) hDAT binding (minimum hDATbinding). Total binding is defined by addition of 5 μl of binding bufferalone in the presence of [³H] WIN-35,428. Stock solutions of compoundsto be tested were prepared in DMSO at concentrations of 10 mM to 10 uM.On the day of assay, test compounds were diluted in assay bufferaccording to test range (100,000 to 10 nM) ensuring a maximal DMSOconcentration of less than 0.5% in the assay reaction wells. Homogenizedmembranes were pre-incubated with test compounds for 20 min at 4° C.before the initiation of the binding reaction. The binding reaction isinitiated by addition of 25 μl of ³[H]-WIN 35,428 diluted in bindingbuffer. The final concentration of ³[H]-WIN 35,428 delivered was 10 nM.The K_(D) value estimated for ³[H]-WIN-35,428 in hDAT membranes(Lot#296-083-A) was 6.9 nM. The radioligand concentration, [L], used inthe competition binding assays is a factor difference of 1.4 compared tothe K_(D) value and was used to calculate the K_(i) value. The platecontaining the radioligand binding reactions were incubated for 2 h at4° C. on a shaking table (Bellco, Vineland, N.J.) at 3 revolutions perminute. The MultiScreen-FB opaque 96-well filtration plates containedMillipore glass fiber filters (Millipore glass fiber B, Cat. No.MAFBN0B) were used to terminate the binding reactions and to separatebound from free radioligand. The plates were presoaked with 0.5%polyethylenimine (PEI; Sigma Cat. No. P-3143) in water for a minimum oftwo hours at room temperature to reduce nonspecific binding of ³[H]-WIN35,428 during the harvest procedure. Before harvesting the reactionplates, the PEI solution is aspirated from the filter plates using avacuum manifold. Aliquots of each reaction (90 μl of each 100 μlreaction well) were transferred from the reaction plates to the filterplates using a Zymark Rapid Plate-96 automated pipette station. Thebinding reaction is terminated by vacuum filtration through the glassfiber filters. The filter plates were aspirated at 5-10 inches of Hg,and the wells are washed 9 times with 200 μl wash buffer (50 mMTris-HCl, 0.9% NaCl, pH 7.4; 4° C.) using a 12 channel aspiration/washsystem. Plastic bottom supports are removed from the filter plates andthe plates are placed in plastic liners. A 100 μl aliquot ofscintillation fluid was added to each well and the top of each plate issealed with adhesive film. The plates are vigorously shaken at 5 rpm for10-15 minutes to ensure adequate equilibration of aqueous to solventpartitioning. The collection of raw counts per minute (cpm) data wasdone using a Wallac Microbeta counter (Perkin Elmer).

Evaluation of Results

For each experiment, a data stream of cpm values collected from theWallac Microbeta counter was downloaded to a Microsoft Excel statisticalapplication program. Calculations of IC₅₀ values were made using thetransformed-both-sides logistic dose response program that uses mean cpmvalues from wells representing maximum binding (total)(assay buffer) andmean cpm values from wells representing minimum binding (NSB, 10 μMmazindol). Estimation of the IC₅₀ values was completed on a log scaleand the line was fit between the maximum and minimum binding values. TheK_(i) value is a function of the concentration of the compound requiredto inhibit 50% of the radioligand (IC₅₀ value) divided by the freeradioligand concentration [L] divided by the K_(D) value plus one(K_(i)=IC₅₀/(1+[L]/K_(D))). The K_(i) value for these studies wasdetermined by dividing the IC₅₀ value by a factor of 2.4 to account forthe concentration of ³[H]-WIN 35,428 used in the assay.

Results are shown in the following table:

TABLE A hDAT hNET Binding RLM Structure Function IC50 stabilityCHEMISTRY IC50 (nM) (nM) t½ (min)

3.8 1908.2 11

1.9 671.4 12

5.3 6204.5 10

6.4 4967.7 9

9.1 5455.3 7

4.2 2625.5 7

394.0 >30

9.7 509.1 7

2.9 2158.5 6

99.6 997.5 >30

18.4 3185.2 >30

327.7 262.3 >30

146.0 386.1 >30

294.0 1871.8 6

64.0 2325.5 5

143.0 267.1 29

104.0 >1000 pending

When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges specific embodiments thereinare intended to be included.

The disclosures of each patent, patent application and publication citedor described in this document are hereby incorporated herein byreference, in its entirety.

Those skilled in the art will appreciate that numerous changes andmodifications can be made to the preferred embodiments of the inventionand that such changes and modifications can be made without departingfrom the spirit of the invention. It is, therefore, intended that theappended claims cover all such equivalent variations as fall within thetrue spirit and scope of the invention.

1. A compound of formula I:

or a tautomer or pharmaceutically acceptable salt thereof; wherein: n isan integer from 0 to 4; m is an integer from 1 to 6; X is —CH₂—; R¹ is,independently at each occurrence, H, alkyl, alkoxy, halo, CF₃, OCF₃,hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl,heteroaryl, alkylsulfoxide, alkylsulfone, alkylsulfonamide,arylsulfonamide alkylamido, or arylamido; wherein each aryl orheteroaryl is independently substituted with 0-3 alkyl, alkoxy, halo,CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynylgroups; and each arylsulfonamide or arylamido is independentlysubstituted with 0-3 alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy,alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide,alkylsulfone, alkylsulfonamide, or alkylamido groups; R² is aryl orheteroaryl substituted with 0-4 alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy,alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide,alkylsulfone, alkylsulfonamide, arylsulfonamide, alkylamido, arylamido,or aryl or heteroaryl optionally substituted with alkyl, alkoxy, halo,CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl; R³and R⁴ are, independently, H, alkyl, arylalkyl or heteroarylmethyl,wherein each of alkyl, arylalkyl or heteroarylmethyl are indepentylsubstituted with 0-3 alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy,alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups, provided thatneither R³ or R⁴ contain an aminoalkyl group;

represents an S-isomer, R-isomer or racemate; and wherein 1-3 carbonatoms in ring A may optionally be replaced with N.
 2. The compound ofclaim 1, wherein each R¹ is H.
 3. The compound of claim 1, wherein R²is:

wherein, each R⁵, R⁶, R⁷, R⁸ and R⁹ are independently selected from thegroup consisting of H, alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy,alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl substituted,heteroaryl, alkylsulfoxide, alkylsulfone, alkylsulfonamide,arylsulfonamide, alkylamido, or arylamido.
 4. The compound of claim 3,wherein R⁹ is F.
 5. The compound of claim 4, wherein R⁵, R⁶, R⁷ and R⁸are H.
 6. The compound of claim 3, wherein R⁵, R⁶, R⁷, R⁸ and R⁹ are H,halo, alkyl or alkoxy.
 7. The compound of claim 1, wherein R³ is methyl.8. The compound of claim 1, wherein R⁴ is H.
 9. The compound of claim 1,wherein m is an integer from 2 to
 6. 10. The compound of claim 1,wherein m is
 2. 11. The compound of claim 1, wherein ring A comprisesall carbon atoms.
 12. The compound of claim 1, wherein R² is pyridinyl,methyl-pyridinyl, ethyl-pyridinyl, methoxy-pyridinyl, or quinolinyl. 13.The compound of claim 1, wherein R² is phenyl, fluoro-phenyl,difluoro-phenyl, trifluoro-phenyl, chloro-phenyl, fluoro-chloro-phenyl,bromo-phenyl, trifluoromethyl-phenyl trifluoromethoxy-phenyl,methyl-fluoro-phenyl, methoxy-fluoro-phenyl, or naphthyl.
 14. Thecompound of claim 1, wherein

represents an S-isomer.
 15. The compound of claim 1, wherein

represents an R-isomer.
 16. The compound of claim 3, wherein: R¹ is H;R⁹ is F; R⁵, R⁶, R⁷ and R³ are H; R³ is methyl; R⁴ is H; m is 2; and

represents an S-isomer.
 17. The compound of claim 1, selected from thegroup consisting of:


18. The compound of claim 1, selected from the group consisting of:1-amino-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;(2R)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;(2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;3-fluoro-4-{3-[(3S)-3-hydroxy-4-(methylamino)butyl]-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl}phenol:4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)pentan-2-ol;(2S)-1-amino-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;(2S)-5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)pentan-2-ol;(2R)-5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)pentan-2-ol;4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(ethylamino)butan-2-ol;1-(dimethylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol;4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(isopropylamino)butan-2-ol;1-(cyclopropylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol;1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol;4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylamino)butan-2-ol;(2R)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylamino)butan-2-ol;(2S)-1-(dimethylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol;(2R)-1-(dimethylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol;(2S)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(isopropylamino)butan-2-ol;(2R)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(isopropylamino)butan-2-ol;(2S)-1-(cyclopropylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol;(2S)-1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol;(2R)-1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol;(2S)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(ethylamino)butan-2-ol;(2R)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(ethylamino)butan-2-ol;(2S)-1-(cyclopropylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;(2S)-1-(cyclopropylamino)-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;(2S)-1-(cyclopropylamino)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;(2S)-1-(cyclopropylamino)-4-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;(2S)-1-(cyclopropylamino)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;(2S)-1-(cyclopropylamino)-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;(2S)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylamino)butan-2-ol;(2S)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;(2S)-4-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;(2S)-4-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;(2S)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;(2S)-4-[3-(4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;(2S)-1-(methylamino)-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;(2S)-4-[3-(2-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;(2S)-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;(2R)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;(2R)-4-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;(2R)-4-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;(2R)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;(2R)-4-[3-(4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;(2R)-1-(methylamino)-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;(2R)-4-[3-(2-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;(2R)-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;(2S)-1-(cyclobutylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;(2S)-1-(cyclopentylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;(2S)-1-(cyclohexylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;(2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(isopropylamino)butan-2-ol;(2S)-1-(ethylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;and pharmaceutically acceptable salts thereof.
 19. The compound of claim1, wherein said pharmaceutically acceptable salt is a hydrochloride ordihydrochloride.
 20. A composition, comprising: a. at least one compoundof formula I:

or a tautomer or pharmaceutically acceptable salt thereof; wherein: n isan integer from 0 to 4; m is an integer from 1 to 6; X is —CH₂—; R¹ is,independently at each occurrence, H, alkyl, alkoxy, halo, CF₃, OCF₃,hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl,heteroaryl, alkylsulfoxide, alkylsulfone, alkylsulfonamide,arylsulfonamide alkylamido, or arylamido; wherein each aryl orheteroaryl is independently substituted with 0-3 alkyl, alkoxy, halo,CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynylgroups; and each arylsulfonamide or arylamido is independentlysubstituted with 0-3 alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy,alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide,alkylsulfone, alkylsulfonamide, or alkylamido groups; R² is aryl orheteroaryl substituted with 0-4 alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy,alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide,alkylsulfone, alkylsulfonamide, arylsulfonamide, alkylamido, arylamido,or aryl or heteroaryl optionally substituted with alkyl, alkoxy, halo,CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl; R³and R⁴ are, independently, H, alkyl, arylalkyl or heteroarylmethyl,wherein each of alkyl, arylalkyl or heteroarylmethyl are indepentylsubstituted with 0-3 alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy,alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups, provided thatneither R³ or R⁴ contain an aminoalkyl group;

represents an S-isomer, R-isomer or racemate; and wherein 1-3 carbonatoms in ring A may optionally be replaced with N; and b. at least onepharmaceutically acceptable carrier.
 21. A method for treating orpreventing a condition selected from the group consisting of a vasomotorsymptom, sexual dysfunction, gastrointestinal disorder, genitourinarydisorder, chronic fatigue syndrome, fibromyalgia syndrome, depressiondisorder, endogenous behavioral disorder, cognitive disorder, diabeticneuropathy, pain, and combinations thereof in a subject in need thereof,comprising the step of: administering to said subject an effectiveamount of a compound of formula I:

or a tautomer or pharmaceutically acceptable salt thereof; wherein: n isan integer from 0 to 4; m is an integer from 1 to 6; X is —CH₂—; R¹ is,independently at each occurrence, H, alkyl, alkoxy, halo, CF₃, OCF₃,hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl,heteroaryl, alkylsulfoxide, alkylsulfone, alkylsulfonamide,arylsulfonamide alkylamido, or arylamido; wherein each aryl orheteroaryl is independently substituted with 0-3 alkyl, alkoxy, halo,CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynylgroups; and each arylsulfonamide or arylamido is independentlysubstituted with 0-3 alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy,alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide,alkylsulfone, alkylsulfonamide, or alkylamido groups; R² is aryl orheteroaryl substituted with 0-4 alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy,alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide,alkylsulfone, alkylsulfonamide, arylsulfonamide, alkylamido, arylamido,or aryl or heteroaryl optionally substituted with alkyl, alkoxy, halo,CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl; R³and R⁴ are, independently, H, alkyl, arylalkyl or heteroarylmethyl,wherein each of alkyl, arylalkyl or heteroarylmethyl are indepentylsubstituted with 0-3 alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy,alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups, provided thatneither R³ or R⁴ contain an aminoalkyl group;

represents an S-isomer, R-isomer or racemate; and wherein 1-3 carbonatoms in ring A may optionally be replaced with N.
 22. The method ofclaim 21, wherein said vasomotor symptom is hot flush.
 23. The method ofclaim 21, wherein said sexual dysfunction is desire-related orarousal-related.
 24. The method of claim 21, wherein saidgastrointestinal disorder or said genitourinary disorder is stressincontinence or urge incontinence.
 25. The method of claim 21, whereinsaid condition is chronic fatigue syndrome or fibromyalgia syndrome. 26.The method of claim 20, wherein said condition is a depression disorderselected from the group consisting of major depressive disorder,generalized anxiety disorder, panic disorder, attention deficit disorderwith or without hyperactivity, sleep disturbance, social phobia, andcombinations thereof.
 27. The method of claim 21, wherein said conditionis diabetic neuropathy.
 28. The method of claim 21, wherein saidcondition is pain.
 29. The method of claim 28, wherein said pain isacute centralized pain, acute peripheral pain, or a combination thereof.30. The method of claim 28, wherein said pain is chronic centralizedpain, chronic peripheral pain, or a combination thereof.
 31. The methodof claim 28, wherein said pain is neuropathic pain, visceral pain,musculoskeletal pain, bony pain, cancer pain, inflammatory pain, or acombination thereof.
 32. The method of claim 31, wherein saidneuropathic pain is associated with diabetes, post traumatic pain ofamputation, lower back pain, cancer, chemical injury, toxins, majorsurgery, peripheral nerve damage due to traumatic injury compression,post-herpetic neuralgia, trigeminal neuralgia, lumbar or cervicalradiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflexsympathetic dystrophy, casualgia, thalamic syndrome, nerve rootavulsion, reflex sympathetic dystrophy or post thoracotomy pain,nutritional deficiencies, viral infection, bacterial infection,metastatic infiltration, adiposis dolorosa, burns, central painconditions related to thalamic conditions, or a combination thereof. 33.The method of claim 32, wherein said neuropathic pain is post-herpeticneuralgia.
 34. The method of claim 31, wherein said visceral pain isassociated with ulcerative colitis, irritable bowel syndrome, irritablebladder, Crohn's disease, rheumatologic (arthralgias), tumors,gastritis, pancreatitis, infections of the organs, biliary tractdisorders, or a combination thereof.
 35. The method of claim 28, whereinsaid subject is female; and the pain is female-specific pain.